Dr. Arun Mukherjee, MD
Sr. Consultant in Medicine, Shubham Hospital, Kalkaji, New Delhi
Director, FSMHP-UDAAN Autism Project, C/27-28 Dayanand Colony, New Delhi-24
Dr. I C Verma, FRCP, FAAP, FAMS
Sr. Consultant & Chairman, Dept. of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi
Autism is a form of disability causing delayed neurodevelopment in which children are born apparently normal, and within 18 to 36 months of age, regress to a lower level of
psychosocial skills, mental faculties, communication skills, and acquire dysfunction of sensory integration and behavior.
The test drug (MB12 Injedtion 25 mg/ml containing only a safe natural biodegradable preservative and no thiomerosal, aluminium or other potentially harmful preservative) is likely to be supplied to selected 100 children only, at
We have negotiated with an ISO:9001 certified Internationally accredited Lab to get all tests done at a rebate.
The children selected for the study will have to come at a
pre-designated week (1st, 2nd, 3rd or 4th),
once in 3 months, for 3 working days (Monday to Friday evening), for 3 years, to get assessed,
tests carried out as necessary for drug therapy monitoring, and to receive
the drugs supply for next 3 months only, as they are short shelf life
drugs. Non-compliant children will be dropped from the study and will be not have further access to the
test drugs till it is approved and made commercially available.
All parents MUST bring their own Ice Box / Igloo large
enough to carry 30 Insulin Syringes pre-filled with correct dose MB12 as
per weight of child, each time they visit us.
All tests must be done only at designated laboratory
branches of Religare (formerly SRL Ranbaxy Labs). No tests done anywhere else are acceptable as per our research
protocol as submitted to Drugs Controller of India.
The parents will need to arrange sponsorship/donation of a subsidized cost for their assessments
at UDAAN-INDIRA (SI, Speech, OT, Cognitive tests, DSM-IV, CARS, VABS and secretarial / logistic expenses at UDAAN), Sir Ganga Ram Hospital
Dept. Dept. of Genetics (Genetic counseling and medical advice where appropriate), Dieticians counseling, medical checkups, and final guidance
Results of most tests, except a few confidential tests (these, too, would be available during the Humanitarian phase of the study) and follow up are planned to become available through email for benefit of the parents and their pediatricians.
All children will be randomly allocated to one of two groups. Both will receive GFCF diet, micronutrient support and recommended (by us) Standard Therapies for 3 to 6 months. Thereafter, as per randomization code, the child may receive either the test drug or placebo for six months. After six months., the rate of change in neurodevelopment will be assessed, the code will be broken for that child, and then the Humanitarian phace will start. During this phase, all responders (in the test drug group) and all in the Placebo group will receive the test drug for a total of three years at significant rebate, as long as the child is brought to UDAAN for the 3-monthly check ups.
Throughput the study period, it shall be COMPULSORY for each child to carry out Standard Therapy under duly qualified experienced team of therapists as per gtuidelines to be given by UDAAN. Defaulters will be removed from the study.
Parents may opt for Standard Therapy at our premises or at our sattelite center at NIODA or at theur home town at a recognizxed Therapy center.
Recognised Therapy Centers of Autism, with necessary staff, equipment including full and proper facilities and staff for Sensory Integration and Autism specialized Special Educators, may join this project as research partners, subject to the opinion of the Research team
The objective of this study is to try to improve their developmental standards and quality of life in phases of intervention as mentioned above.
No other medication (Homeopathy, Ayurvedic, Unani, Allopathic tonics, etc.) will be allowed to be used except as advised by Investigative Team Medical Personnel.
Pre-Trial Health Management
It is well known that malnutrition, ill health, gut infection or infestations, and an unbalanced diet can make a child behave abnormally. Hence, the first phase of the study, lasting 3 to 6 months, shall focus on restoring the child to normal health, free of infections, infestations and allergic reactions.
Based on the biochemical tests, allergy panel study, and stool culture, the child will be guided to take a hypo-allergic diet, free of gluten and casein, with avoidance of food the child does not tolerate, along with standard easily available vitamin / mineral / iron supplements at doses recommended.
Intensive Occupational Therapy, Sensory Integration Therapy, Special Education, Speech Therapy, etc, must be provided to all children, as per laid down Standard Therapy
protocols followed in all Autism management centers
Assessments will be done at 3-month intervals throughout drug administration phases, to assess the improvement in quality of life and improvement in cognitive and communication skills, and psychosocial behavior in the children, with the aid of the sequential addition of various medical interventions.
This study is designed to investigate early medical interventions using MB12 in otherwise healthy children with autism in India
Medical Interventions proposed
Vitamin MB12 Therapy
In the process of intestinal absorption and subsequent transfer into peripheral tissue, folic acid is converted into Dihydrofolate (DHF) by the Dihydrofolate Reductase enzyme (DHFR). DHF is then metabolized into Tetrahydrofolate (THF) again by DHFR. THF is metabolized into 5,10-Methylene-THF. The 5,10-Methylene-THF is converted to L-methylfolate by the Methyl Tetra Hydro Folate Reductase enzyme (MTHFR).
The methyl radical is transferred to Vitamin B12 (Vitamin MB12), which helps convert Homocysteine to Methionine, which then transfers the methyl radical for methylation of DNA, RNA, Protein
Membrane Phospholipids and Creatine, while the remnant molecule again goes on to form Homocysteine ==> Cysteine ==> Glutathione with help of the Pyridoxal system. One of the genetic deficiencies seen in many children with Autism is relative deficiency of the key enzyme MTHFR
This deficiency may be suspected by testing blood for MTHFR Polymorphism.
Deficiency of Vitamin MB12 manufacture leads to defective neural activity. US reports suggest that symptoms of such deficiency and its amelioration with supplement of vitamin MB12
subcutaneous injections, is recorded in about 60 % of autism affected children. Blood MTHFR Polymorphism status can be tested at Delhi
Vitamin MB12 has negligible storage in the body, though the parent compound ordinary B12 has. Any dose of MB12 given by oral, IM or IV route reaches peak blood levels very
fast and, after handing over the methyl fracation, gets converted to ordinary Vitamin B12 which does not have the same activity as MB12. Even though ordinary Vitamin B12 is stored in the body for a long time, it is absolutely not the same as sustained Methyl B12. Thus, ordinary shots of MB12 and tablets of MB12 cannot achieve the mandatory low but sustained flat blood level of vitamin MB12 to efficiently manufacture a continuous 24 hour level of adequate amounts of Methionine from homocysteine by the MTHFR route.
In USA, an specific level concentrated formulation of Vitamin MB12 is used to reduce the required volume of the subcutaneously injected drug (tiny surface area so very slow absorption rate),
which is injected subcutaneously into the gluteal fat (low blood supply hence very slow absorption), to delay absorption rate to get a low flat sustained blood level for 3 days per shot, as needed. In addition, this area also has a low sensory nerve supply, hence injection site pain is also very low.
It is expected that this will restore vitamin MB12 levels, methionine levels and DNA/RNA signaling mechanisms, to reduce severity of the autistic state, as measured by the standard scales for children with autism.
Children provisionally diagnosed as Autism, attending the OPDs of Sir Ganga Ram Hospital Genetics OPD or UDAAN for the Disabled Center, or other authorised and recognized (By UDAAN) competent authority.
Confirmation of diagnosis using DSM IV criteria by panel Psychiatrist / Psychologist, PLUS evaluation by CARS and VABS done by panel specialist only (to maintain uniformity of standard). For the sake of uniformity of severity, we are looking for a CARS score of 35 or more.
Age 2 to 6 years, belonging to either sex.
Well-educated parents who can understand the experimental nature of the study, and can give informed voluntary written permission for inclusion of their autistic child for this study, and who would be able to arrange sponsoships / donations for tests to be done at 3 month intervals at designated laboratories (we have arranged significant rebate), drugs to be purchased at highly subsidized rates to be supplied by the manufacturer, and sponsorships / donations for meeting the costs of registration, assessments, secretarial and logistic expenses at UDAAN for the Disabled Center.
Children having other genetic disabilities, cerebral palsy or any other form of direct brain injury that coincidentally has some Autistic features.
Insufficiency of liver / kidney / marrow function as per appropriate biochemical tests.
Any chronic uncontrolled illness that may need medical therapy which could interfere with diagnosis, treatment and assessment of the Autism symptoms.
Allergy to S/C injections of vitamin Methyl B12.
No. of Children to be enrolled 100.
Duration of Study: 30 months.
Children meeting all inclusion and exclusion criteria and selected for the study will be assessed every three months for a range of biochemical parameters, based on DAN Protocol of the Autism Research Center, USA, as per our proforma enclosed. The children will also be assessed clinically for Cognitive parameters using internationally approved scales (CARS, VABS, Sensory Profile, ASEBA, etc.) as applicable to a particular child, Motor parameters using GMFM and other appropriate scales as appropriate and Speech parameters using similarly approved scales.
Each child will be continually be monitored to improve his/her general health using a balanced non-allergenic well tolerated diet, avoidance of foods that do not suit the child, administration of standard off-the-shelf multi-vitamins and mineral supplementations (copper-free to the extent possible), and isolation and treatment of inter-current infections if any.
Throughout the two to three years of follow up, each child will be actively encouraged to maintain a high standard of Standard Therapy as a baseline permanent therapeutic intervention, irrespective of group.
As per US experience, it is expected that the S/C Injections of Vitamin MB12, after reviving the neural pathways, will cause increased sensory input from the periphery, which will initially overwhelm the deficient sensory integration mechanisms of the child, leading to a temporary aggravation of misbehavior, increased chewing and tantrums. These withdrawal symptom-like clinical features are expected to subside in less than 6 weeks, followed by gradual and progressive improvement in all symptoms of autism.
A similar over-reaction to sensory revival is expected at the start of GFCF Diet.
A careful watch will be kept on the children to ensure that these self limiting phases of aggravation do not become unmanageable. In such cases, the drug or procedure may be withdrawn temporarily to overcome its problems. Re-introduction may be attempted under lower dose, and then titrated as per tolerance.
The data will be analyzed using standard statistical methods to assess the benefit to risk ratio of each phase.
(DELETED AS CONFIDENTIAL)
DOUBLE BLIND PLACEBO CONTROLLED RANDOMISED STUDY TO EVALUATE
THE SAFETY AND EFFICACY OF VITAMIN MB12 AND CHELATION OF EXCESSIVE HEAVY METAL
IN BODY REDUCING SEVERITY OF AUTISM IN AFFECTED CHILDREN
ORIGINAL COPY FOR PARENT / LEGAL GUARDIAN AND ONE COPY FOR INSTITUTION
Protocol No: UDAAN/AUTISM/.................
Initial of Child: ______; Name of Child: _________________________________
Name of Parent / Legal Guardian ______________________________________
Date of Birth / Age: _________________; Sex M [__] / F [__]
Please initial box (Subject)
I confirm that I have read and understood the information sheet attached, for the above study and have had the opportunity to ask questions.
I understand that my participation in the study is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected.
I understand that the Sponsor of the clinical trial, others working on behalf of the Sponsor, the Ethics Committee and the regulatory authorities will not need my permission to look at my health records both in respect of the current study and any further research that may be conducted in relation to it, even if I withdraw from the trial.
I agree to this access. However, I understand that my identity will not be revealed in any information released to third parties or published.
I agree not to restrict the use of any data or results that arise from this study provided such a use is only for scientific purpose(s)
I agree to allow my child, ___________ to take part in the above study.
Signature of the Parent/Legally Acceptable Representative: _______________; Date: _____/_____/______
Name of Signatory: ___________________________
Relation to child enrolled for the study: __________________
Signature of the Investigator: __________________; Date: _____/_____/______
Name of Study Investigator: ________________________________
Signature of the Witness ______________________ Date: ____/_____/_______
Name of the Witness: _____________________________________
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