Trial Outcomes & Findings for Clinical Study for the Treatment of Breast Cancer: the Patient Will Receive Afatinib Plus Letrozole or Letrozole Alone (NCT NCT02115048)

Last Updated: 2019-12-26

Results Overview

Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by Response Evaluation Criteria in Solid Tumors - RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, the randomization date for each patient was the "start date". If the status at the last assessment date was "Non-complete response/ Non-progressive disease" or "Complete response", then the patient was considered "censored". If the status at the last assessment for any tumor was "Progressive disease", then the patient was considered as having an event. Progressive disease is defined using RECIST v1 .1 as a ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more target or non-target new lesions and/or unequivocal progression of existing non-target lesions.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

44 participants

Primary outcome timeframe

Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Results posted on

2019-12-26

Participant Flow

For all patients consented on the trial, a tumor sample was sent to the central lab for testing of ER/PR and HER2 and determination of the H-score. This was assessed prior to randomization. Patients with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-score between 1 and 159 entered screening phase.

Participant milestones

Participant milestones
Measure	Arm A Letrozole 2.5 mg	Arm B Letrozole 2.5 mg + Afatinib 30 mg
Overall Study STARTED	23	21
Overall Study COMPLETED	23	21
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A n=23 Participants Letrozole 2.5 mg	Arm B n=21 Participants Letrozole 2.5 mg + Afatinib 30 mg	Total n=44 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=23 Participants	0 Participants n=21 Participants	0 Participants n=44 Participants
Age, Categorical Between 18 and 65 years	14 Participants n=23 Participants	10 Participants n=21 Participants	24 Participants n=44 Participants
Age, Categorical >=65 years	9 Participants n=23 Participants	11 Participants n=21 Participants	20 Participants n=44 Participants
Sex: Female, Male Female	23 Participants n=23 Participants	21 Participants n=21 Participants	44 Participants n=44 Participants
Sex: Female, Male Male	0 Participants n=23 Participants	0 Participants n=21 Participants	0 Participants n=44 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Romania	3 participants n=23 Participants	5 participants n=21 Participants	8 participants n=44 Participants
Region of Enrollment United States	9 participants n=23 Participants	6 participants n=21 Participants	15 participants n=44 Participants
Region of Enrollment Bosnia and Herzegovina	4 participants n=23 Participants	3 participants n=21 Participants	7 participants n=44 Participants
Region of Enrollment Spain	7 participants n=23 Participants	7 participants n=21 Participants	14 participants n=44 Participants
Menopausal Status Pre-Menopausal	0 Participants n=23 Participants	0 Participants n=21 Participants	0 Participants n=44 Participants
Menopausal Status Post-Menopausal	23 Participants n=23 Participants	21 Participants n=21 Participants	44 Participants n=44 Participants
ECOG Performance Status 0	12 Participants n=23 Participants	14 Participants n=21 Participants	26 Participants n=44 Participants
ECOG Performance Status 1	11 Participants n=23 Participants	7 Participants n=21 Participants	18 Participants n=44 Participants
Weight (kg)	77.39 kg STANDARD_DEVIATION 16.25 • n=23 Participants	69.59 kg STANDARD_DEVIATION 11.14 • n=21 Participants	73.67 kg STANDARD_DEVIATION 14.44 • n=44 Participants

PRIMARY outcome

Timeframe: Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Population: The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed (including PFS).

Outcome measures

Outcome measures
Measure	Arm A n=18 Participants Letrozole 2.5 mg	Arm B n=18 Participants Letrozole 2.5 mg + Afatinib 30 mg
Progression Free Survival (PFS) Censored	14 Participants	16 Participants
Progression Free Survival (PFS) Failed (Progressed or Died)	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Under treatment: every 4 wks up to 9 months (average) for subject in the Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months

Overall Survival is defined as the time from randomization until death to any cause. For subjects in which treatment is discontinued for reasons different than Progression Disease: after treatment and up to documentation of disease progression: Overall Survival is assessed every 12 weeks

Outcome measures

Outcome measures
Measure	Arm A n=18 Participants Letrozole 2.5 mg	Arm B n=18 Participants Letrozole 2.5 mg + Afatinib 30 mg
Overall Survival (OS) Died	2 Participants	0 Participants
Overall Survival (OS) Censored	16 Participants	18 Participants

SECONDARY outcome

Timeframe: Tumor assessment: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Objective response rate (ORR) is defined as the proportion of randomized subjects achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST). As per RECIST (version 1.1): CR is defined as disappearance of all target and non target lesions - lymph node (LN) \<10mm. PR is defined as at least a 30% decrease in the Sum of Diameters, taking as reference the Baseline Sum of Diameters

Outcome measures

Outcome measures
Measure	Arm A n=18 Participants Letrozole 2.5 mg	Arm B n=18 Participants Letrozole 2.5 mg + Afatinib 30 mg
Objective Response Rate (ORR) Complete Response (CR)	2 Participants	1 Participants
Objective Response Rate (ORR) Death	2 Participants	0 Participants
Objective Response Rate (ORR) Progessive Disease (PD)	2 Participants	2 Participants
Objective Response Rate (ORR) Non-CR / Non-PD	12 Participants	15 Participants

SECONDARY outcome

Timeframe: Tumor assessments: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Population: The timeframe specifies when tumor assessments were performed. Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore data for TTP was not produced due to the small number of patients (evaluation would not produce meaningful data).

As per Response Evaluation Criteria In Solid Tumors (RECIST). Time to progression (TTP) is defined as the time interval from date of randomization to date of the first documented objective tumor progression.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Under treatment: every 4 wks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months

Population: Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are listed. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are presented.

Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are presented. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are listed by treatment arm. Adverse events were tabulated by system organ class, preferred term and toxicity grade by treatment arm. For subjects in which treatment was discontinued for reasons different than progression of disease, the assessment was conducted every 12 weeks following treatment, and up to documentation of disease progression. \*\* Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed. Adverse event data collected are described per arm but no statistical comparison was made.

Outcome measures

Outcome measures
Measure	Arm A n=23 Participants Letrozole 2.5 mg	Arm B n=21 Participants Letrozole 2.5 mg + Afatinib 30 mg
Number of Participants With Adverse Events Patient having at least one TEAE	16 Participants	20 Participants
Number of Participants With Adverse Events Patient having at least one serious TEAE	5 Participants	2 Participants
Number of Participants With Adverse Events At least one TEAE related to afatinib	0 Participants	18 Participants
Number of Participants With Adverse Events At least one TEAE related to letrozole	6 Participants	11 Participants
Number of Participants With Adverse Events At least one serious TEAE related to letrozole	0 Participants	0 Participants
Number of Participants With Adverse Events At least one serious TEAE related to afatinib	0 Participants	1 Participants
Number of Participants With Adverse Events Patient having at least one grade 3/4 TEAE	7 Participants	3 Participants
Number of Participants With Adverse Events TEAE leading to discontinuation - letrozole	1 Participants	1 Participants
Number of Participants With Adverse Events TEAE leading to discontinuation - afatinib	0 Participants	1 Participants
Number of Participants With Adverse Events Fatal TEAE	0 Participants	0 Participants

Adverse Events

Arm A

Serious events: 5 serious events

Other events: 16 other events

Deaths: 2 deaths

Arm B

Serious events: 2 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm A n=23 participants at risk Letrozole 2.5 mg	Arm B n=21 participants at risk Letrozole 2.5 mg + Afatinib 30 mg
Gastrointestinal disorders Enteritis	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	4.8% 1/21 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Gastrointestinal disorders Haematemesis	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Gastrointestinal disorders Nausea	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
General disorders Pyrexia	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	4.8% 1/21 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	4.8% 1/21 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Infections and infestations Cellulitis	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Infections and infestations Sepsis	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Injury, poisoning and procedural complications Multiple Fractures	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal Cell Carcinoma	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant Melanoma in Situ	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Nervous system disorders Subarachnoid Haemorrhage	4.3% 1/23 • Number of events 1 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	0.00% 0/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.

Other adverse events

Additional Information

Director, Project Management

Translational Research In Oncology (TRIO)

Phone: +33 1 58 10 09 09

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee No publication, abstract or presentation of the Study will be made without the approval of the Study Steering Committee (SCC). The SSC will be solely responsible for the analysis, interpretation and public disclosure of the results of the trial in accordance with the statistical plan.
Publication restrictions are in place

Restriction type: OTHER

Measure	Arm A n=23 participants at risk Letrozole 2.5 mg	Arm B n=21 participants at risk Letrozole 2.5 mg + Afatinib 30 mg
Gastrointestinal disorders Diarrhoea	8.7% 2/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	71.4% 15/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Gastrointestinal disorders Nausea	13.0% 3/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	14.3% 3/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Gastrointestinal disorders Stomatitis	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	28.6% 6/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Gastrointestinal disorders Abdominal Distension	4.3% 1/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	9.5% 2/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
General disorders Fatigue	4.3% 1/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	28.6% 6/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Infections and infestations Paronychia	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	28.6% 6/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Infections and infestations Urinary Tract Infection	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	23.8% 5/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Infections and infestations Upper Respiratory Tract Infection	13.0% 3/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	4.8% 1/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Investigations Weight Increased	8.7% 2/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	19.0% 4/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Investigations Weight Decreased	8.7% 2/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	9.5% 2/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Musculoskeletal and connective tissue disorders Arthralgia	17.4% 4/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	9.5% 2/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Musculoskeletal and connective tissue disorders Back Pain	17.4% 4/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	9.5% 2/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Musculoskeletal and connective tissue disorders Bone Pain	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	19.0% 4/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	4.3% 1/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	9.5% 2/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Musculoskeletal and connective tissue disorders Myalgia	8.7% 2/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	4.8% 1/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Skin and subcutaneous tissue disorders Rash	4.3% 1/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	28.6% 6/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Skin and subcutaneous tissue disorders Dry Skin	4.3% 1/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	23.8% 5/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Skin and subcutaneous tissue disorders Dermatitis Acneiform	0.00% 0/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	19.0% 4/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Skin and subcutaneous tissue disorders Pruritus	4.3% 1/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	14.3% 3/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.
Skin and subcutaneous tissue disorders Alopecia	8.7% 2/23 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.	4.8% 1/21 • 4 years, 3 months (28 August 2014 to 30 November 2018). 28 August 2004 corresponds to the first enrolment in the trial, and 30 November 2018 corresponds to the 'end of data' collection period. All participants were assessed for adverse events (AEs) from their date of enrolment to the end of the observation period, which as per protocol is defined as 30 days following their last treatment intake - during this time serious AEs also had to be reported.