Trial Outcomes & Findings for Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis (NCT NCT01733316)

Last Updated: 2024-12-27

Results Overview

The primary analysis of WBC cystine was performed using the natural log transformed WBC cystine level; the log transformation is a normalizing transformation. For each participant, the difference between the morning and corresponding non-morning log WBC cystine value (non-morning minus morning) at each monthly visit during the Cystagon® phase (Months 1, 2, and 3) was computed and these differences were averaged. The average difference between morning and non-morning log WBC cystine value was similarly computed for each participant during the RP103 phase (Months 5, 6, and 7). The primary analysis compared within-subject pairs (Cystagon® phase paired with RP103 phase) of non-morning minus morning average differences of log WBC cystine level.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

41 participants

Primary outcome timeframe

While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-morning (AM) and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-evening (PM) dose.

Results posted on

2024-12-27

Participant Flow

Participant milestones

Participant milestones
Measure	All Participants Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® every 6 hours (Q6H). RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 every 12 hours (Q12H). Long Term Phase: On or after Month 7, for the remainder of study participants received RP103 Q12H.
Cystagon® Phase STARTED	41
Cystagon® Phase COMPLETED	41
Cystagon® Phase NOT COMPLETED	0
RP103 Phase STARTED	41
RP103 Phase COMPLETED	40
RP103 Phase NOT COMPLETED	1
Long Term Extension Phase STARTED	38
Long Term Extension Phase COMPLETED	33
Long Term Extension Phase NOT COMPLETED	5

Reasons for withdrawal

Reasons for withdrawal
Measure	All Participants Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® every 6 hours (Q6H). RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 every 12 hours (Q12H). Long Term Phase: On or after Month 7, for the remainder of study participants received RP103 Q12H.
RP103 Phase Non-compliance	1
Long Term Extension Phase Adverse Event	1
Long Term Extension Phase Consent Withdrawn by Subject	2
Long Term Extension Phase Sponsor Decision	2

Baseline Characteristics

Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=41 Participants Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® Q6H. RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 Q12H. Long Term Phase: On or after Month 7, for the remainder of study participants received RP103 Q12H.
Age, Continuous	24.5 years STANDARD_DEVIATION 11.56 • n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants

PRIMARY outcome

Timeframe: While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-morning (AM) and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-evening (PM) dose.

Population: Pharmacodynamic (PD) Analysis Set: All participants who received at least one treatment of Cystagon® and RP103 and who had at least one WBC cystine level recorded after each of Cystagon® treatment and RP103 treatment. Only participants with an average difference during both the Cystagon® and RP103 phases were included.

Outcome measures

Outcome measures
Measure	Cystagon® Phase n=40 Participants From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.	RP103 Phase n=40 Participants During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.	Long-Term Phase From Month 7 and for the remainder of study: participants received RP103 Q12H. Observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.
Average Difference Between Morning and Non-Morning Log White Blood Cell (WBC) Cystine Values	-0.229 log [nmol ½ cystine/mg protein] Standard Deviation 0.5027	0.080 log [nmol ½ cystine/mg protein] Standard Deviation 0.3939	—

SECONDARY outcome

Timeframe: From first dose of study drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30 - 1350) during the long-term RP-103 phase.

Population: Safety Analysis Set: all participants who received at least 1 dose of study drug (RP103). The row "At least 1 TEAE" includes both serious and non-serious AEs.

AE: any untoward medical occurrence that does not necessarily have a causal relationship with study drug. SAE: any untoward medical occurrence that at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is medically significant, and though not included in the above list, is an important medical event, according to the Investigator. Treatment-emergent adverse events (TEAEs) occurred after first dose of study drug. Clinically significant abnormalities in laboratory values (hematology, blood chemistry, urinalysis), electrocardiograms (ECGs), vital signs, and physical examinations were to be reported as adverse events and so are included in this summary of TEAEs

Outcome measures

Outcome measures
Measure	Cystagon® Phase n=41 Participants From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.	RP103 Phase n=41 Participants During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.	Long-Term Phase n=38 Participants From Month 7 and for the remainder of study: participants received RP103 Q12H. Observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs At least 1 TEAE leading to discontinuation	0 Participants	0 Participants	1 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs At least 1 TEAE	31 Participants	38 Participants	32 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs At least 1 TEAE-related to study drug	4 Participants	20 Participants	18 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs At least 1 grade ≥ 3 TEAE	5 Participants	4 Participants	13 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs At least 1 serious TEAE	5 Participants	6 Participants	13 Participants

SECONDARY outcome

Timeframe: While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose

Population: PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.

Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of dimethylsulfide (DMS) in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state pharmacokinetic (PK) samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.

Outcome measures

Outcome measures
Measure	Cystagon® Phase n=20 Participants From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.	RP103 Phase During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.	Long-Term Phase From Month 7 and for the remainder of study: participants received RP103 Q12H. Observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.
Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine Cystagon® dosing period	3.5 mg/L Standard Deviation 1.87	—	—
Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine RP103 dosing period	2.9 mg/L Standard Deviation 1.65	—	—

SECONDARY outcome

Population: PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.

Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.

Outcome measures

Outcome measures
Measure	Cystagon® Phase n=20 Participants From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.	RP103 Phase During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.	Long-Term Phase From Month 7 and for the remainder of study: participants received RP103 Q12H. Observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.
Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine Cystagon® dosing period	1.2 hour Standard Deviation 0.87	—	—
Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine RP103 dosing period	3.2 hour Standard Deviation 1.30	—	—

SECONDARY outcome

Population: PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.

Outcome measures

Outcome measures
Measure	Cystagon® Phase n=20 Participants From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.	RP103 Phase During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.	Long-Term Phase From Month 7 and for the remainder of study: participants received RP103 Q12H. Observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.
Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine Cystagon® dosing period	7.8 hr*mg/L Standard Deviation 5.18	—	—
Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine RP103 dosing period	9.4 hr*mg/L Standard Deviation 4.86	—	—

SECONDARY outcome

Timeframe: While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose 30 min post-dose, 2, 3, 4 and 6 hours post-dose. While taking RP103 (Month 4, 5, or 7): Within 15 min. prior to morning dose. 1, 2, 3, 4, 5, 6, 8, 10, 12 hours post dose

Population: PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.

Outcome measures

Outcome measures
Measure	Cystagon® Phase n=20 Participants From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.	RP103 Phase During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.	Long-Term Phase From Month 7 and for the remainder of study: participants received RP103 Q12H. Observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.
Halitosis Substudy: Expired Air DMS Concentrations Cystagon®, within 15 minutes prior to dose	4.7 nmol/L Standard Deviation 5.54	—	—
Halitosis Substudy: Expired Air DMS Concentrations Cystagon®, 30 minutes post dose	4.7 nmol/L Standard Deviation 4.75	—	—
Halitosis Substudy: Expired Air DMS Concentrations Cystagon®, 1 hour post morning dose	6.9 nmol/L Standard Deviation 6.75	—	—
Halitosis Substudy: Expired Air DMS Concentrations Cystagon®, 2 hours post morning dose	11.9 nmol/L Standard Deviation 11.26	—	—
Halitosis Substudy: Expired Air DMS Concentrations Cystagon®, 3 hours post morning dose	11.2 nmol/L Standard Deviation 13.32	—	—
Halitosis Substudy: Expired Air DMS Concentrations Cystagon®, 4 hours post morning dose	8.8 nmol/L Standard Deviation 12.05	—	—
Halitosis Substudy: Expired Air DMS Concentrations Cystagon®, 6 hours post morning dose	4.4 nmol/L Standard Deviation 3.77	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, within 15 minutes prior to dose	4.6 nmol/L Standard Deviation 6.05	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 1 hour post morning dose	5.4 nmol/L Standard Deviation 7.71	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 2 hours post morning dose	5.1 nmol/L Standard Deviation 6.28	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 3 hours post morning dose	7.7 nmol/L Standard Deviation 8.53	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 4 hours post morning dose	8.6 nmol/L Standard Deviation 11.22	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 5 hours post morning dose	11.2 nmol/L Standard Deviation 15.86	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 6 hours post morning dose	8.5 nmol/L Standard Deviation 13.87	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 8 hours post morning dose	5.7 nmol/L Standard Deviation 10.76	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 10 hours post morning dose	5.2 nmol/L Standard Deviation 8.13	—	—
Halitosis Substudy: Expired Air DMS Concentrations RP103, 12 hours post morning dose	4.3 nmol/L Standard Deviation 5.32	—	—

Adverse Events

Cystagon® Phase

Serious events: 5 serious events

Other events: 28 other events

Deaths: 0 deaths

RP103 Phase

Serious events: 6 serious events

Other events: 33 other events

Deaths: 0 deaths

Long-Term Phase

Serious events: 13 serious events

Other events: 32 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Evelyn Olson, Director

Horizon Pharma USA, Inc.

Phone: 224-383-3000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Horizon requests that any investigator/institution that plans on presenting/publishing results provide written notification of their request 60 days prior to their presentation/publication. Horizon requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if Horizon needs to secure patent or proprietary protection.
Publication restrictions are in place

Restriction type: OTHER