Trial Outcomes & Findings for Efficacy and Safety of CIP-Isotretinoin in Patients With Severe Recalcitrant Nodular Acne (NCT NCT00975143)

Last Updated: 2014-07-04

Results Overview

The change from Baseline to Week 20 in the total number of nodular lesions was calculated as the Week 20 lesion count minus Baseline lesion count and compared using Analysis of Covariance (ANCOVA), controlling for Baseline total nodular lesion count, gender and analysis site. The 95% CI of the adjusted least square mean difference (CIP-ISOTRETINOIN minus Isotretinoin) was also calculated using the ANCOVA model. Pre-defined criterion for non-inferiority: upper bound of the 95% CI for the treatment difference \< 4.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

925 participants

Primary outcome timeframe

20 weeks

Results posted on

2014-07-04

Participant Flow

The study was performed at 49 investigational centers in the United States and Canada. Of the 1265 patients screened for the study, a total of 925 were randomized to CIP-Isotretinoin (N=464) or generic Isotretinoin (N=461) between October 2009 and October 2010. Randomization was stratified by gender and study site.

Reasons for screen failure: patient's decision (83 pts), low disease severity (61), entry criteria (51), psychological disqualification (44), lost to follow-up (33) and low vitamin D levels (33). Washouts were specified for: systemic corticosteroids, spironolactone (30 d), other acne treatment, phenytoin (14 d), topical corticosteroids (7 d).

Participant milestones

Participant milestones
Measure	CIP-Isotretinoin CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks
Overall Study STARTED	464	461
Overall Study Completed Treatment (Week 20)	403	410
Overall Study COMPLETED	394	401
Overall Study NOT COMPLETED	70	60

Reasons for withdrawal

Reasons for withdrawal
Measure	CIP-Isotretinoin CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks
Overall Study Adverse Event	19	15
Overall Study Withdrawal by Subject	15	15
Overall Study Lost to Follow-up	20	16
Overall Study Non-compliance	5	8
Overall Study Physician Decision	1	2
Overall Study Details not available	10	4

Baseline Characteristics

Efficacy and Safety of CIP-Isotretinoin in Patients With Severe Recalcitrant Nodular Acne

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CIP-Isotretinoin n=464 Participants CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin n=461 Participants (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Total n=925 Participants Total of all reporting groups
Age, Categorical <=18 years	205 Participants n=5 Participants	192 Participants n=7 Participants	397 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	259 Participants n=5 Participants	269 Participants n=7 Participants	528 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	20.8 years STANDARD_DEVIATION 7.5 • n=5 Participants	20.7 years STANDARD_DEVIATION 6.8 • n=7 Participants	20.8 years STANDARD_DEVIATION 7.2 • n=5 Participants
Sex: Female, Male Female	187 Participants n=5 Participants	178 Participants n=7 Participants	365 Participants n=5 Participants
Sex: Female, Male Male	277 Participants n=5 Participants	283 Participants n=7 Participants	560 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	59 Participants n=5 Participants	63 Participants n=7 Participants	122 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	405 Participants n=5 Participants	398 Participants n=7 Participants	803 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	380 participants n=5 Participants	373 participants n=7 Participants	753 participants n=5 Participants
Region of Enrollment Canada	84 participants n=5 Participants	88 participants n=7 Participants	172 participants n=5 Participants
Nodular Lesion Count	18.4 Lesions STANDARD_DEVIATION 14.7 • n=5 Participants	17.7 Lesions STANDARD_DEVIATION 10.8 • n=7 Participants	18.0 Lesions STANDARD_DEVIATION 12.9 • n=5 Participants
Inflammatory Lesion Count	37.8 Lesions STANDARD_DEVIATION 31.3 • n=5 Participants	38.4 Lesions STANDARD_DEVIATION 34.5 • n=7 Participants	38.1 Lesions STANDARD_DEVIATION 33.0 • n=5 Participants
Physician's Global Severity Assessment (PGSA) 1 (Almost clear)	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants
Physician's Global Severity Assessment (PGSA) 2 (Mild)	11 participants n=5 Participants	10 participants n=7 Participants	21 participants n=5 Participants
Physician's Global Severity Assessment (PGSA) 3 (Moderate)	49 participants n=5 Participants	60 participants n=7 Participants	109 participants n=5 Participants
Physician's Global Severity Assessment (PGSA) 4 (Severe)	329 participants n=5 Participants	322 participants n=7 Participants	651 participants n=5 Participants
Physician's Global Severity Assessment (PGSA) 5 (Very Severe)	64 participants n=5 Participants	63 participants n=7 Participants	127 participants n=5 Participants
Physician's Global Severity Assessment (PGSA) Not assessed	8 participants n=5 Participants	4 participants n=7 Participants	12 participants n=5 Participants

PRIMARY outcome

Timeframe: 20 weeks

Population: Analysis based on the Per Protocol (PP) Population, defined as all randomized patients who were at least 75% compliant with their assigned treatment, had no major study protocol violations, had a Week 20 count of total nodular lesions, and did not use any disallowed medications during the 20 study weeks.

Outcome measures

Outcome measures
Measure	CIP-Isotretinoin n=363 Participants CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin n=361 Participants (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks
Co-primary Outcome 1: Change From Baseline in Total Nodular Lesion Count (Facial and Truncal)	-17.01 Lesions Standard Deviation 14.26 • Interval -0.2712 to 0.5475	-16.52 Lesions Standard Deviation 10.57 • Interval -1.1337 to 3.5338

PRIMARY outcome

Timeframe: 20 weeks

The percentage of patients in each group who achieved ≥90% reduction in the total nodular lesion count from Baseline to Week 20 was calculated along with its 95% CI (normal approximation). A 95% 2-sided CI on the difference between treatments (CIP-ISOTRETINOIN minus Isotretinoin) was also computed. Pre-defined criterion for non-inferiority: lower bound of the 95% CI for the treatment difference \> -10.

Outcome measures

Outcome measures
Measure	CIP-Isotretinoin n=363 Participants CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin n=361 Participants (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks
Co-Primary Outcome 2: Proportion of Patients Who Achieve at Least a 90% Reduction in Total Number of Nodular Lesions (Facial and Truncal).	78.8 percentage of participants Interval 74.6 to 83.0	80.9 percentage of participants Interval 76.8 to 84.9

SECONDARY outcome

Timeframe: 20 weeks

Population: Analysis based on the Per Protocol (PP) Population. Patients with a Baseline PGSA score of 0 or 1 (i.e., who had primarily truncal lesions at Baseline) were excluded from the analysis, as PGSA evaluated facial lesions.

PGSA categories: 1 (Almost clear); 2 (Mild); 3 (Moderate); 4 (Severe); 5 (Very severe). A grade of either 0 (clear) or 1 (almost clear) on the 6-point PGSA scale within the Week 20 analysis window was considered a success.

Outcome measures

Outcome measures
Measure	CIP-Isotretinoin n=348 Participants CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin n=349 Participants (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks
Proportion of Patients Who Are Rated as Clear/Almost Clear on the Six-point Physicians' Global Assessment Scale (PGSA).	85.9 percentage of participants Interval 82.3 to 89.6	89.4 percentage of participants Interval 86.2 to 92.6

Adverse Events

CIP-Isotretinoin

Serious events: 7 serious events

Other events: 428 other events

Deaths: 0 deaths

Isotretinoin

Serious events: 5 serious events

Other events: 413 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	CIP-Isotretinoin n=464 participants at risk CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin n=460 participants at risk (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks
Gastrointestinal disorders Abdominal pain	0.22% 1/464 • Number of events 7 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.00% 0/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Gastrointestinal disorders Abdominal pain upper	0.22% 1/464 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.00% 0/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
General disorders Chest pain	0.00% 0/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.22% 1/460 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Hepatobiliary disorders Cholelithiasis	0.00% 0/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.22% 1/460 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Infections and infestations Orchitis	0.22% 1/464 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.00% 0/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Infections and infestations Varicella	0.00% 0/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.22% 1/460 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Injury, poisoning and procedural complications Ligament rupture	0.22% 1/464 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.00% 0/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Nervous system disorders Migraine	0.22% 1/464 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.00% 0/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Pregnancy, puerperium and perinatal conditions Pregnancy	0.22% 1/464 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.22% 1/460 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Psychiatric disorders Substance abuse	0.22% 1/464 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.00% 0/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	0.22% 1/460 • Number of events 1 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).

Other adverse events

Additional Information

Julia Chan, RAC

Cipher Pharmaceuticals Inc.

Phone: 905-602-5840

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	CIP-Isotretinoin n=464 participants at risk CIP-Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks	Isotretinoin n=460 participants at risk (Generic) Isotretinoin 10 mg and 20 mg capsules taken with meals, at an initial titration dose of approximately 0.5 mg/kg/day, divided into 2 doses for the first 4 weeks, followed by approximately 1 mg/kg/day divided into 2 doses for 16 weeks
Gastrointestinal disorders Lip dry	45.0% 209/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	45.7% 210/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Skin and subcutaneous tissue disorders Dry skin	44.2% 205/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	44.8% 206/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Musculoskeletal and connective tissue disorders Back pain	20.7% 96/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	19.3% 89/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Eye disorders Dry eye	18.8% 87/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	17.0% 78/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Musculoskeletal and connective tissue disorders Arthralgia	13.8% 64/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	13.0% 60/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Respiratory, thoracic and mediastinal disorders Epistaxis	11.6% 54/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	9.1% 42/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Nervous system disorders Headache	8.0% 37/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	7.8% 36/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Infections and infestations Nasopharyngitis	7.8% 36/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	10.4% 48/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Gastrointestinal disorders Chapped lips	7.3% 34/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	7.0% 32/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Skin and subcutaneous tissue disorders Dermatitis	6.0% 28/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	5.0% 23/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Investigations Blood creatine kinase increased	5.6% 26/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	5.9% 27/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Gastrointestinal disorders Cheilitis	5.6% 26/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	4.1% 19/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Musculoskeletal and connective tissue disorders Musculoskeletal discomfort	5.4% 25/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	3.5% 16/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Infections and infestations Upper respiratory tract infection	5.4% 25/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	3.0% 14/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).
Eye disorders Visual acuity reduced	5.0% 23/464 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).	5.4% 25/460 • AEs and SAEs were collected from the beginning of double-blind treatment until 30 days after the last study treatment (Week 24). AEs occurring before starting study treatment but after signing the informed consent form were recorded under Medical History. Adverse events were analyzed based on the Safety Population (defined as all randomized patients who consumed at least one dose of study medication, including those for whom dosing information was unknown), based on the actual treatment received. The Safety Population included 924 patients (CIP-Isotretinoin 464, Isotretinoin 460).