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Trial record 8 of 115 for:    acne AND almost

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

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ClinicalTrials.gov Identifier: NCT00975143
Recruitment Status : Completed
First Posted : September 11, 2009
Results First Posted : July 4, 2014
Last Update Posted : July 4, 2014
Sponsor:
Information provided by (Responsible Party):
Cipher Pharmaceuticals Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Severe Nodular Acne
Interventions Drug: CIP-Isotretinoin
Drug: Isotretinoin
Enrollment 925
Recruitment Details 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.
Pre-assignment Details 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).
Arm/Group Title CIP-Isotretinoin Isotretinoin
Hide Arm/Group Description 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 (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
Period Title: Overall Study
Started 464 461
Completed Treatment (Week 20) 403 410
Completed 394 401
Not Completed 70 60
Reason Not Completed
Adverse Event             19             15
Withdrawal by Subject             15             15
Lost to Follow-up             20             16
Non-compliance             5             8
Physician Decision             1             2
Details not available             10             4
Arm/Group Title CIP-Isotretinoin Isotretinoin Total
Hide Arm/Group Description 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 (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 of all reporting groups
Overall Number of Baseline Participants 464 461 925
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 464 participants 461 participants 925 participants
<=18 years
205
  44.2%
192
  41.6%
397
  42.9%
Between 18 and 65 years
259
  55.8%
269
  58.4%
528
  57.1%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 464 participants 461 participants 925 participants
20.8  (7.5) 20.7  (6.8) 20.8  (7.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 464 participants 461 participants 925 participants
Female
187
  40.3%
178
  38.6%
365
  39.5%
Male
277
  59.7%
283
  61.4%
560
  60.5%
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 464 participants 461 participants 925 participants
Hispanic or Latino
59
  12.7%
63
  13.7%
122
  13.2%
Not Hispanic or Latino
405
  87.3%
398
  86.3%
803
  86.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Ethnicity was designated as Hispanic or Non-Hispanic.
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 464 participants 461 participants 925 participants
United States 380 373 753
Canada 84 88 172
Nodular Lesion Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Lesions
Number Analyzed 464 participants 461 participants 925 participants
18.4  (14.7) 17.7  (10.8) 18.0  (12.9)
[1]
Measure Description: Qualified medical practitioners, blinded to treatment group assignment made counts of nodules in the facial and truncal area. Where possible, the same individual performed all evaluations for a patient.
Inflammatory Lesion Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Lesions
Number Analyzed 464 participants 461 participants 925 participants
37.8  (31.3) 38.4  (34.5) 38.1  (33.0)
[1]
Measure Description: Qualified medical practitioners, blinded to treatment group assignment made counts of inflammatory lesions (papules and pustules) in the facial and truncal area. Where possible, the same individual performed all evaluations for a patient.
Physician's Global Severity Assessment (PGSA)   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 464 participants 461 participants 925 participants
1 (Almost clear) 3 2 5
2 (Mild) 11 10 21
3 (Moderate) 49 60 109
4 (Severe) 329 322 651
5 (Very Severe) 64 63 127
Not assessed 8 4 12
[1]
Measure Description: Acne severity status was graded by the investigator on a 6-point scale, from 0 = Clear (No nodules, pustules or papules visible) to 5 = Very Severe (Highly inflammatory acne covering the affected area, with many nodules and cysts present ). The PGSA was applied to facial lesions only (ie, not conducted on patients with only truncal lesions).
1.Primary Outcome
Title Co-primary Outcome 1: Change From Baseline in Total Nodular Lesion Count (Facial and Truncal)
Hide Description

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.

Time Frame 20 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title CIP-Isotretinoin Isotretinoin
Hide Arm/Group Description:
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
(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 Number of Participants Analyzed 363 361
Mean (Standard Deviation)
Unit of Measure: Lesions
-17.01  (14.26) -16.52  (10.57)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection CIP-Isotretinoin, Isotretinoin
Comments Change from Baseline was calculated as the post-Baseline value minus the Baseline value
Type of Statistical Test Non-Inferiority or Equivalence
Comments Pre-defined criterion for non-inferiority: upper bound of the 95% CI for the treatment difference < 4.
Statistical Test of Hypothesis P-Value 0.5077
Comments P values are from analysis of covariance (ANCOVA) controlling for Baseline total nodular lesion count, gender and analysis site.
Method ANCOVA
Comments The 95% CI of the adjusted least square mean difference (CIP-ISOTRETINOIN minus Isotretinoin) was calculated using the ANCOVA model.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.1382
Confidence Interval (2-Sided) 95%
-0.2712 to 0.5475
Estimation Comments [Not Specified]
2.Primary Outcome
Title Co-Primary Outcome 2: Proportion of Patients Who Achieve at Least a 90% Reduction in Total Number of Nodular Lesions (Facial and Truncal).
Hide Description

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.

Time Frame 20 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title CIP-Isotretinoin Isotretinoin
Hide Arm/Group Description:
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
(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 Number of Participants Analyzed 363 361
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
78.8
(74.6 to 83.0)
80.9
(76.8 to 84.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection CIP-Isotretinoin, Isotretinoin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Pre-defined criterion for non-inferiority: lower bound of the 95% CI for the treatment difference > -10.
Statistical Test of Hypothesis P-Value >0.05
Comments [Not Specified]
Method Normal approximation
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion difference
Estimated Value -2.10
Confidence Interval (2-Sided) 95%
-7.94 to 3.74
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Proportion of Patients Who Are Rated as Clear/Almost Clear on the Six-point Physicians' Global Assessment Scale (PGSA).
Hide Description 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.
Time Frame 20 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title CIP-Isotretinoin Isotretinoin
Hide Arm/Group Description:
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
(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 Number of Participants Analyzed 348 349
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
85.9
(82.3 to 89.6)
89.4
(86.2 to 92.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection CIP-Isotretinoin, Isotretinoin
Comments The analysis of the secondary efficacy endpoint was based on observed cases only, with no imputation for missing values.
Type of Statistical Test Non-Inferiority or Equivalence
Comments If the two co-primary endpoints were significant, a 95% 2 sided CI on the difference between treatments (CIP-Isotretinoin minus Isotretinoin) was calculated.
Statistical Test of Hypothesis P-Value >0.05
Comments [Not Specified]
Method Normal approximation
Comments 95% CI on difference in proportions (CIP-Isotretinoin minus Isotretinoin) was estimated using normal approximation.
Method of Estimation Estimation Parameter Proportion difference
Estimated Value -3.48
Confidence Interval (2-Sided) 95%
-8.4 to 1.4
Estimation Comments [Not Specified]
Time Frame 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 Event Reporting Description 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).
 
Arm/Group Title CIP-Isotretinoin Isotretinoin
Hide Arm/Group Description 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 (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
All-Cause Mortality
CIP-Isotretinoin Isotretinoin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
CIP-Isotretinoin Isotretinoin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/464 (1.51%)      5/460 (1.09%)    
Gastrointestinal disorders     
Abdominal pain  1  1/464 (0.22%)  7 0/460 (0.00%)  0
Abdominal pain upper  1  1/464 (0.22%)  1 0/460 (0.00%)  0
General disorders     
Chest pain  1  0/464 (0.00%)  0 1/460 (0.22%)  1
Hepatobiliary disorders     
Cholelithiasis  1  0/464 (0.00%)  0 1/460 (0.22%)  1
Infections and infestations     
Orchitis  1  1/464 (0.22%)  1 0/460 (0.00%)  0
Varicella  1  0/464 (0.00%)  0 1/460 (0.22%)  1
Injury, poisoning and procedural complications     
Ligament rupture  1  1/464 (0.22%)  1 0/460 (0.00%)  0
Nervous system disorders     
Migraine  1  1/464 (0.22%)  1 0/460 (0.00%)  0
Pregnancy, puerperium and perinatal conditions     
Pregnancy  1  1/464 (0.22%)  1 1/460 (0.22%)  1
Psychiatric disorders     
Substance abuse  1  1/464 (0.22%)  1 0/460 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Asthma  1  0/464 (0.00%)  0 1/460 (0.22%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
CIP-Isotretinoin Isotretinoin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   428/464 (92.24%)      413/460 (89.78%)    
Eye disorders     
Dry eye  1  87/464 (18.75%)  78/460 (16.96%) 
Visual acuity reduced  1  23/464 (4.96%)  25/460 (5.43%) 
Gastrointestinal disorders     
Lip dry  1  209/464 (45.04%)  210/460 (45.65%) 
Chapped lips  1  34/464 (7.33%)  32/460 (6.96%) 
Cheilitis  1  26/464 (5.60%)  19/460 (4.13%) 
Infections and infestations     
Nasopharyngitis  1  36/464 (7.76%)  48/460 (10.43%) 
Upper respiratory tract infection  1  25/464 (5.39%)  14/460 (3.04%) 
Investigations     
Blood creatine kinase increased  1  26/464 (5.60%)  27/460 (5.87%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  96/464 (20.69%)  89/460 (19.35%) 
Arthralgia  1  64/464 (13.79%)  60/460 (13.04%) 
Musculoskeletal discomfort  1  25/464 (5.39%)  16/460 (3.48%) 
Nervous system disorders     
Headache  1  37/464 (7.97%)  36/460 (7.83%) 
Respiratory, thoracic and mediastinal disorders     
Epistaxis  1  54/464 (11.64%)  42/460 (9.13%) 
Skin and subcutaneous tissue disorders     
Dry skin  1  205/464 (44.18%)  206/460 (44.78%) 
Dermatitis  1  28/464 (6.03%)  23/460 (5.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 12.1
Generic isotretinoin control because Accutane® was discontinued in the US. 201 PPP exclusions (CIP-Isotretinoin 101, Isotretinoin 100) due to discontinuation < Week 20 (61+51), non-compliance with treatment (76+75) or other requirements (≥1 reason).
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Julia Chan, RAC
Organization: Cipher Pharmaceuticals Inc.
Phone: 905-602-5840 ext 326
Responsible Party: Cipher Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT00975143     History of Changes
Other Study ID Numbers: ISOCT.08.01
First Submitted: September 9, 2009
First Posted: September 11, 2009
Results First Submitted: July 4, 2012
Results First Posted: July 4, 2014
Last Update Posted: July 4, 2014