Severe Nodular Acne
Conditions
Keywords
isotretinoin, dermatology, skin
Brief summary
The purpose of this study is to compare the efficacy and safety of CIP-Isotretinoin and a marketed (generic) formulation of isotretinoin when both are administered twice daily with meals.
Interventions
DRUGCIP-Isotretinoin
0.5 mg/kg/day for 4 weeks, and 1 mg/kg/day for 16 weeks, taken orally, twice daily.
DRUGIsotretinoin
0.5 mg/kg/day for 4 weeks, and 1 mg/kg/day for 16 weeks, taken orally, twice daily.
Sponsors
Cipher Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 54 Years
Healthy volunteers
No
Inclusion criteria
* Severe recalcitrant nodular acne, which in the opinion of the investigator is compatible with isotretinoin treatment. * Ten (10) or more nodular lesions (facial and/or truncal). * Treatment-naïve patients without any prior exposure to systemic isotretinoin or other retinoids. * Age between 12 and 54 years. * Weight between 40 and 110 kg. * Negative serum human chorionic gonadotropin (hCG) pregnancy test consistent with a non-pregnant state (females only). * No significant disease or clinically significant finding in a physical examination. * No clinically significant abnormal laboratory value. * No clinically significant abnormal vital sign measurement. * Patients presenting with stable and controlled diabetes mellitus (Types I and II) may be included in the study. However, patients should not have had a hospitalization for any diabetes related complications in the last 12 months, and must be on stable medication for the preceding 6 months. To be included in the study, the patients should have Hemoglobin-A1c values ≤ 6.5% at screening and in the test done 3 - 4 months previously. * Patients with previously diagnosed Polycystic Ovarian Syndrome (PCOS) may be included in the study if in the opinion of the investigator they do not have any other clinically significant abnormality (e.g. metabolic syndrome or elevated lipids).
Exclusion criteria
* Female patients will be excluded from the study if they: * Are pregnant; * Are at high risk for becoming pregnant or likely to become pregnant during treatment; * Will be breast-feeding or considering breast feeding during the course of the study. * Known history or presence of any clinically significant unstable medical condition(s) which in the opinion of the investigator could pose a risk for the safety of the patient including any previous history of gastrointestinal disease. * Patients with any skin disease or other condition that might interfere with the evaluation of recalcitrant nodular acne. * Patients will be interviewed using the SCID-CT current and lifetime modules for Major Depression, Mania, and Psychosis. Patients with a lifetime history of psychosis will be excluded. Patients with a history of major depressive, manic, hypomanic or mixed episodes will not be excluded unless they have had an episode during the preceding year. * Patients with any past or current psychotic symptoms. * Patients reporting any suicidal behaviour (including attempts, interrupted attempts, aborted attempts, or other preparatory behaviours), within the past year, or serious suicidal ideation in the past year, will be excluded from study participation. * A lifetime history of wishing to be dead, non-specific active suicidal thoughts or active suicidal ideation without intent to act will not result in exclusion. * Known history or suspected carcinoma. * Known history of liver or kidney disorders (hepatic and renal insufficiency). * Known history or current pseudotumor cerebri (benign intracranial hypertension). * Patients with HLA-B27 related disease, rheumatoid arthritis, rickets or other vitamin D depletion disease or phosphate metabolic disease, severe scoliosis \> 15 Cobb angle, history of back surgery/injuries, ongoing use of anticonvulsants known to affect bone metabolism and other genetic or acquired rheumatologic and joint diseases. * All pediatric patients with serum 25-hydroxyvitamin D levels \< 20 ng/mL. * Patients with hearing disorders who in the opinion of the investigator would not be able to participate in audiometric testing for the study. * Hypersensitivity or idiosyncratic reaction to isotretinoin, Vitamin A and/or any other drug substances with similar activity. * Allergy to soy beans, soy bean oil or any other ingredients in the study medications. * On a special diet within four weeks prior to drug administration (e.g., liquid, protein, raw food diet). * Difficulty consuming two (2) meals a day to sustain weight and health.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-primary Outcome 1: Change From Baseline in Total Nodular Lesion Count (Facial and Truncal) | 20 weeks | 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. |
| Co-Primary Outcome 2: Proportion of Patients Who Achieve at Least a 90% Reduction in Total Number of Nodular Lesions (Facial and Truncal). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Are Rated as Clear/Almost Clear on the Six-point Physicians' Global Assessment Scale (PGSA). | 20 weeks | 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. |
Countries
Canada, United States
Participant flow
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).
Participants by arm
| Arm | Count |
|---|---|
| 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 | 464 |
| 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 | 461 |
| Total | 925 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 19 | 15 |
| Overall Study | Details not available | 10 | 4 |
| Overall Study | Lost to Follow-up | 20 | 16 |
| Overall Study | Non-compliance | 5 | 8 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Withdrawal by Subject | 15 | 15 |
Baseline characteristics
| Characteristic | CIP-Isotretinoin | Total | Isotretinoin |
|---|---|---|---|
| Age, Categorical <=18 years | 205 Participants | 397 Participants | 192 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 259 Participants | 528 Participants | 269 Participants |
| Age, Continuous | 20.8 years STANDARD_DEVIATION 7.5 | 20.8 years STANDARD_DEVIATION 7.2 | 20.7 years STANDARD_DEVIATION 6.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 59 Participants | 122 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 405 Participants | 803 Participants | 398 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Inflammatory Lesion Count | 37.8 Lesions STANDARD_DEVIATION 31.3 | 38.1 Lesions STANDARD_DEVIATION 33 | 38.4 Lesions STANDARD_DEVIATION 34.5 |
| Nodular Lesion Count | 18.4 Lesions STANDARD_DEVIATION 14.7 | 18.0 Lesions STANDARD_DEVIATION 12.9 | 17.7 Lesions STANDARD_DEVIATION 10.8 |
| Physician's Global Severity Assessment (PGSA) 1 (Almost clear) | 3 participants | 5 participants | 2 participants |
| Physician's Global Severity Assessment (PGSA) 2 (Mild) | 11 participants | 21 participants | 10 participants |
| Physician's Global Severity Assessment (PGSA) 3 (Moderate) | 49 participants | 109 participants | 60 participants |
| Physician's Global Severity Assessment (PGSA) 4 (Severe) | 329 participants | 651 participants | 322 participants |
| Physician's Global Severity Assessment (PGSA) 5 (Very Severe) | 64 participants | 127 participants | 63 participants |
| Physician's Global Severity Assessment (PGSA) Not assessed | 8 participants | 12 participants | 4 participants |
| Region of Enrollment Canada | 84 participants | 172 participants | 88 participants |
| Region of Enrollment United States | 380 participants | 753 participants | 373 participants |
| Sex: Female, Male Female | 187 Participants | 365 Participants | 178 Participants |
| Sex: Female, Male Male | 277 Participants | 560 Participants | 283 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 428 / 464 | 413 / 460 |
| serious Total, serious adverse events | 7 / 464 | 5 / 460 |
Outcome results
Primary
Co-primary Outcome 1: Change From Baseline in Total Nodular Lesion Count (Facial and Truncal)
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
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CIP-Isotretinoin | Co-primary Outcome 1: Change From Baseline in Total Nodular Lesion Count (Facial and Truncal) | -17.01 Lesions | Standard Deviation 14.26 |
| Isotretinoin | Co-primary Outcome 1: Change From Baseline in Total Nodular Lesion Count (Facial and Truncal) | -16.52 Lesions | Standard Deviation 10.57 |
Comparison: Change from Baseline was calculated as the post-Baseline value minus the Baseline valuep-value: 0.507795% CI: [-0.2712, 0.5475]ANCOVA
Primary
Co-Primary Outcome 2: Proportion of Patients Who Achieve at Least a 90% Reduction in Total Number of Nodular Lesions (Facial and Truncal).
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CIP-Isotretinoin | 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 |
| Isotretinoin | Co-Primary Outcome 2: Proportion of Patients Who Achieve at Least a 90% Reduction in Total Number of Nodular Lesions (Facial and Truncal). | 80.9 percentage of participants |
p-value: >0.0595% CI: [-7.94, 3.74]Normal approximation
Secondary
Proportion of Patients Who Are Rated as Clear/Almost Clear on the Six-point Physicians' Global Assessment Scale (PGSA).
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CIP-Isotretinoin | Proportion of Patients Who Are Rated as Clear/Almost Clear on the Six-point Physicians' Global Assessment Scale (PGSA). | 85.9 percentage of participants |
| Isotretinoin | Proportion of Patients Who Are Rated as Clear/Almost Clear on the Six-point Physicians' Global Assessment Scale (PGSA). | 89.4 percentage of participants |
Comparison: The analysis of the secondary efficacy endpoint was based on observed cases only, with no imputation for missing values.p-value: >0.0595% CI: [-8.4, 1.4]Normal approximation