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Oral Liquid 13-cis-retinoic Acid (13-CRA) (My-CRA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03291080
Recruitment Status : Active, not recruiting
First Posted : September 25, 2017
Last Update Posted : July 23, 2019
Information provided by (Responsible Party):
Nova Laboratories Limited

Tracking Information
First Submitted Date  ICMJE July 19, 2017
First Posted Date  ICMJE September 25, 2017
Last Update Posted Date July 23, 2019
Actual Study Start Date  ICMJE April 17, 2018
Estimated Primary Completion Date August 28, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2017)
PK- Relative bioavailability (population pharmacokinetic measures) [ Time Frame: On day 1 and 14 of treatment ]
Non-linear, mixed effects modelling approach to determine the relative bioavailability and pharmacokinetics of 13-CRA administered as oral liquid and capsule formulations.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03291080 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2017)
  • Time to maximum concentration (Tmax) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter
  • Maximum plasma concentration (Cmax) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter
  • Area under plasma concentration time curve (AUC) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter
  • Half-life (t1/2) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter
  • Clearance (CL/F) [ Time Frame: On day 1 and 14 of treatment ]
    To determine clearance pharmacokinetics of 13-CRA
  • Volume of distribution (V/F) [ Time Frame: On day 1 and 14 of treatment ]
    To determine volume of distribution pharmacokinetics of 13-CRA
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 19, 2017)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Over 2 months treatment and 14 day follow up ]
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Oral Liquid 13-cis-retinoic Acid (13-CRA)
Official Title  ICMJE Relative Bioavailability and Comparative Pharmacokinetics of 13-CRA Oral Liquid and Extracted Capsule Formulations: a Randomised, Open Label, Multi-dose, Cross-over Clinical Trial in Patients Requiring Treatment Cycles of 13-CRA.
Brief Summary An open label, randomised, multiple dose, cross-over relative bioavailability and pharmacokinetics trial of a novel oral liquid and capsule formulations of 13-CRA administered to patients from 0 months - < 21 years.
Detailed Description

All patients requiring at least two cycles of 13-CRA therapy will be eligible for recruitment into the trial.

13-CRA will be prescribed to patients according to local treatment protocols at each clinical site. The dose administered will be 200mg/m2/day for both test and reference product. Patients with a body weight of ≤12kg will receive a dose of 160 mg/m2.

The pharmacokinetics of 13-CRA liquid (test product) and 200mg/m2/day extracted from capsule (reference product) will be evaluated over two months. Prior to the initiation of 13-CRA treatment as part of the trial, patients will be randomised to receive either liquid or capsule formulation in "My-CRA month 1". The patients will then cross-over to the alternative formulation in "My-CRA month 2". The patients on the trial who require further treatment will revert to standard therapy i.e. 13-CRA extracted from capsules according to local practice.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Neuroblastoma
Intervention  ICMJE
  • Drug: Liquid 13-Cis Retinoic Acid
    Liquid 13-Cis Retinoic Acid
    Other Name: Isotretinoin
  • Drug: Extracted capsules 13-CRA
    Extracted capsules 13-CRA
    Other Name: Isotretinoin
Study Arms  ICMJE
  • Experimental: Liquid
    Oral liquid formulation of 13-Cis Retinoic Acid - test product.
    Intervention: Drug: Liquid 13-Cis Retinoic Acid
  • Experimental: Capsule
    Isotretinoin capsules (13-CRA extracted per standard of care)- reference product.
    Intervention: Drug: Extracted capsules 13-CRA
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 19, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 28, 2019
Estimated Primary Completion Date August 28, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female aged from 0 years to < 21 years of age.
  2. Patient with high risk neuroblastoma, or unresectable, unfavourable histology intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis
  3. Patient who is scheduled to receive at least two treatment cycles of 13-CRA.
  4. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from the capsules).
  5. Negative pregnancy test for females of child-bearing potential before initiation of treatment, and sexually active patients and partners agreeing to undertake adequate contraceptive measures (see section 4.5).
  6. Provision of a single or double lumen central venous catheter for sampling (i.e. already in place).
  7. Parent(s)/legal guardian able and willing to provide written informed consent for the patient to take part in the trial.
  8. Where applicable, the patient should assent to undergo blood sampling for pharmacokinetic purposes and to allow physiological measurements to be made.

Exclusion Criteria:

  1. Any clinically significant medical condition or abnormality, which, in the opinion of the investigator, might compromise the safety of the patient or which might interfere with the trial.
  2. Diagnosis of high-risk neuroblastoma (HRNBL) which is currently being treated on the SIOPEN HRNBL trial (patients who have exited this trial will be eligible).
  3. Known allergy to 13-CRA or any of the excipients.
  4. Inadequate contraception measures in females of childbearing age.
  5. Receiving concomitant treatment with tetracyclines.

Prior to each cycle:

  1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if present, should be stable or improving.
  2. Skin toxicity no greater than CTCAE Grade 1(10)
  3. Serum triglycerides <5.65mmol/L.
  4. No haematuria and / or proteinuria on urinalysis.
  5. Serum calcium ≤ 2.9mmol/L.
  6. Serum creatinine based on age / gender as follows:

    Age Maximum Serum Creatinine µmol/L Male Female 1 month to < 6 months 35 35 6 months to < 1 year 44 44 1 to < 2 years 53 53 2 to < 6 years 70 70 6 to < 10 years 88 88 10 to < 13 years 106 106 13 to < 16 years 132 124

    ≥ 16 years 150 124

  7. Patients with a seizure disorder must be well controlled and taking anticonvulsants. CNS toxicity < grade 2 (CTCAE).

Withdrawal Criteria:

  1. Positive pregnancy test - pregnancy testing will be undertaken before treatment commences and routinely before each course of treatment in females of childbearing potential. If a patient is found to be pregnant during the trial, the next course of treatment will not be given until the pregnancy has been discussed with the treating clinician, and the patient will be withdrawn from the trial whether or not treatment is continued.
  2. Request of the patient, for any reason.
  3. Discretion of the investigator.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03291080
Other Study ID Numbers  ICMJE INV500
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Nova Laboratories Limited
Study Sponsor  ICMJE Nova Laboratories Limited
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Hussain Mulla, PhD Nova Laboratories Limited
PRS Account Nova Laboratories Limited
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP