Beyond Achondroplasia

Growing together with Clara

Phase 3 trial for achondroplasia – BioMarin Study 111-301

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The following information is fully available at the European Union Clinical Trials Register. Some sections will be here highlighted:

1.

Full title of the trial
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia

What does PlaceboRandomized, Double-Blind mean?

Placebo: an inert substance that has no action or effect, but can produce the placebo effect, that is the response that follows the administration of a placebo [1].

Randomized: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. In this particular case, a placebo will be compared with BMN-111 [2].

Double-Blind: when the patient and the investigator are blind in knowledge. This means that neither the patient nor the investigator know which patients are getting the drug and which are getting placebo [3].

2.

Sponsor’s protocol code number 111-301

This is the designation of the phase 3

3.

IMP Role Test

The goal is to test an Investigational medicinal product (IMP)

4.

The IMP has been designated in this indication as an orphan drug in the Community Yes

Any medicinal product that aims to treat a rare disease is designated orphan drug

5.

Description of the IMP
D.3.1 Product name modified recombinant human C-type natriuretic peptide- CNP
D.3.2 Product code BMN 111
D.3.4 Pharmaceutical form Lyophilisate for solution for injection
D.3.4.1 Specific paediatric formulation Yes
D.3.7 Routes of administration for this IMP Subcutaneous use

CNP, is expressed as a 126–amino acid protein precursor (preproCNP), and is then processed to an active 53–amino acid cyclic peptide and further processed to a 22–amino acid peptide.  Native CNP (CNP22) has a short half-life inside the body of less than 2 minutes in mice and humans. BioMarin modified this CNP for a 39–amino acid CNP variant (BMN 111) and is produced in the bacteria Escherichia coli [4].

6.

D.8 Placebo
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo Lyophilisate and solvent for solution for injection
D.8.4 Route of administration of the placebo Subcutaneous use

7.

E.2 Objective of the trial
E.2.1 Main objective of the trial
Evaluate change from baseline in mean annualized growth velocity at 52 weeks in subjects treated with BMN 111 compared with control subjects in the placebo group.
E.2.2 Secondary objectives of the trial
• Evaluate change from baseline in mean height Z-score in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
• Evaluate change from baseline in mean upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
• Evaluate safety and tolerability of BMN 111 in children with ACH
• Evaluate the pharmacokinetics of BMN 111

This study will take 1 year to produce results. Upper:lower segment body ratio will be evaluated.

Upper to lower body ratio

The lower body segment is the measurement of the length from the pubic symphysis (roughly the pubic bone) to the floor; the upper body segment is the height minus the lower body segment. The average U/L ratio (upper body segment : lower body segment) at birth is about 1.7; at age 3 years it is 1.3; at greater than 7 years, it is 1.0 with the upper body segment and lower body segment being about equal. Higher U/L ratios are noted in short-limb dwarfism.

So the ideal is a ratio near 1.

Vitruvian man – Leonardo Da Vinci

8.

Principal inclusion criteria
1. Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of 18 are willing and able to provide written assent (if required by local regulations or the IRB/EC) after the nature of the study has been explained and prior to performance of any research-related procedure.
2. 5 to < 15 years old at study entry
3. Have ACH, documented by clinical grounds and confirmed by genetic testing
4. Have at least a 6-month period of pretreatment growth assessment in Study 111-901 immediately before study entry, and has one documented standing height at least 6 months (+/- 10 days) prior to the screening visit for Study 111-301
5. Females ≥ 10 years old or who have begun menses must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study
6. If sexually active, willing to use a highly effective method of contraception while participating in the study
7. Are ambulatory and able to stand without assistance
8. Are willing and able to perform all study procedures as physically possible
9. Caregivers are willing to administer daily injections to the subjects and complete the required training

All children that participate in this phase 3 study (111-301) have to first take, the natural history/growth assessment study (111-901) for at least 6 months.

9.

End points
E.5.1 Primary end point(s)
The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV) at Week 52 (12- month).
E.5.1.1 Timepoint(s) of evaluation of this end point
Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 29, Week 52
E.5.2 Secondary end point(s)
The secondary efficacy endpoints include the change from baseline in height Z-score and the change from baseline in upper:lower body segment ratio.

Safety will be evaluated by assessment of AEs, SAEs, laboratory test results (urinalysis, chemistry, hematology), changes in vital signs, physical examination, ECG, X-rays/DXA, clinical hip assessment, and anti-BMN 111 immunogenicity assessments.

PK sampling will be carried out over the 12-month study period in subjects randomized to BMN 111 or placebo.

E.5.2.1 Timepoint(s) of evaluation of this end point
Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 29, Week 52

Clinical labs (urinalysis, chemistry, hematology): Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54

Vital signs and AEs: Screen, Day 1, Day 2, Day 3, Day 10, Week 6, Week 26, Week 39, Week 52, Week 54 (follow-up)

Physical exam: Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

ECG: Screen, Day 1, Day 10, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

X-Ray/DXA: Screen, Week 26, Week 52

Clinical hip assessment: Screen, Week 26, Week 52

Anti-BMN 111 immunogenicity: Day 1, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

PK: Day 1 (full), Week 13 (partial), Week 26 (full), Week 39 (partial), Week 52 (full)

Endpoint: In clinical trials, it is an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives.

Anthropometric measurements:  systematic measurements of the size, shape and composition of the body

PK: Pharmacokinetics is the study of ‘what the body does to the drug’ and includes:
•    the rate and extent to which drugs are absorbed into the body and distributed to the body tissues
•    the rate and pathways by which drugs are eliminated from the body by metabolism and excretion
•    the relationship between time and plasma drug concentration [5].

10.

E.8.5 The trial involves multiple Member States Yes
E.8.5.1 Number of sites anticipated in the EEA – Europe 10

11.

E.8E.8.6 Trial involving sites outside the EEA.
Australia
France
Germany
Japan
Spain
Turkey
United Kingdom
United States
E.8.7 Trial has a data monitoring committee – Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial – LVLS

LVLS – Last visit, last subject/patient

12.

F. Population of Trial Subjects- Age Range
F.1.1 Trial has subjects under 18 Yes
F.1.1 Number of subjects for this age range (all world): 110
F.1.1.1 In Utero No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3 Newborns (0-27 days) No
F.1.1.4 Infants and toddlers (28 days-23 months) No
F.1.1.5 Children (2-11years) Yes
F.1.1.5.1 Number of subjects for this age range: 88
F.1.1.6 Adolescents (12-17 years) Yes
F.1.1.6.1 Number of subjects for this age range: 22
F.1.2 Adults (18-64 years) No
F.1.3 Elderly (>=65 years) No

13.

F.4.2 For a multinational trial
F.4.2.1 In the EEA 24
F.4.2.2 In the whole clinical trial 110
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
Following completion of 52 weeks subjects in both treatment groups may be eligible to receive BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over a longer term.

 

 

Bibliography

 

  1. Gupta U, Verma M. Placebo in clinical trials. Perspect Clin Res. 2013 Jan-Mar; 4(1): 49–52
  2. National Cancer Institute dictionary
  3. Misra S. Randomized double blind placebo control studies, the “Gold Standard” in intervention based studies. Indian J Sex Transm Dis. 2012 Jul-Dec; 33(2): 131–134.
  4. US national library of medicine
  5. IUPHAR Pharmacology Education Project
  6. EU Clinical Trials Register

 

3 Comments

  1. tengo una niña con acondroplasia tiene 6 años ya tiene la prueba genética y me gustaría saber que posibilidades hay de que sea `parte de esta etapa de la investigación del BMN 111-

    • Dear Silvia,

      All the contacts of the clinical centers currently enrolling children for the observational study sponsored by BioMarin, can be found in
      clinicaltrials.gov

  2. Suponiendo que estos ensayos llegaran a concluir la eficacia de esta droga, cual seria la fecha aproximada en la q estarian a la venta?

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