DOUBLE BLIND PLACEBO CONTROLLED RANDOMISED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF INJECTION VITAMIN MB12 IN REDUCING SEVERITY OF AUTISM IN AFFECTED CHILDREN UNDERGOING STANDARD THERAPY

GET THE BASICS RIGHT FIRST

Standard Therapy and GFCF is the not the panacea for all ills for an Autistic Child. IT MUST BE BALANCED BY INDIVIDUALLY CORRECTLY ADJUSTED MICRONUTRIENT SUPPORT FOR BEST RESULTS.

There are a plethora of diets suggested for children with Autism Spectrum Disorders.
If you try to follow all of them, and also want a diet balanced for age, sex and weight, and you are in a country like India and most other countries of the world, where specialised "Problem-ingredient"-free foods are hard to come by (e.g. Gluten free diet, etc, etc, etc, ad nauseaum), then YOU ARE IN A FOOL'S PARADISE..... Your child will starve due to malnutrition, as opposed to undernutrition.

Somewhere down the road, you have to be practical and draw a line. In any case, statistics tell us that only up to two-thirds of a population of autistic children respond to any one one particular intervention, which includes a specific dietary restriction. Try a diet for 3 to 6 months. If there is NO CHANGE, try another. If there is a change, how can you be sure it was due to the diet? Reverse the diet for a week, and see what happens. If the child shows any sign or symptom of regression or changed behavior, get back to that diet and stay with it.

Another problem faced by parents is inadequate knowledge of micronutrient support.... for the un-initiated, it means specific, individual child's biochemical test based, and properly interpreted doses of specific vitamins and minerals. The doctor also has to be sure of his knowledge of the pharmacokinetics of the micronutrients he plans to use, including all their drug-to-drug interaction, before giving them to your child. Then you may be more sure that the micronutrients are not given as convenient megadosage multiminerals. Many minerals are absorbed from the same enzymatic pathway, and giving them together retards the absorption of one mineral vs. another. The same goes for carotenoids and some other micronutrients.

The ethnicity of the child also matters. Children of some countries have genetic or otherwise high metabolic rate. That is why some puny size (population-wise) countries produce Olympic Athletics Champions at the drop of a hat but unfortunately none have come out of India, a country of 1 billion+ polulation. Indians excel in games of skill and intellect but only occasionally in physically challenging games.
That leads us to believe that doses of drugs, vitamins and minerals must be tailor-made for countries like India with our lower body size and lower metabolic rate. The megadose vitamins famous and very very highly advertised in USA may not necessarily be what your child in India may require.
However, to be truthful, we do not have any scientific evidence either way because no one has done this research, and we at UDAAN have just started keeping records for the last 2 to 3 years. We are satisfied with our hypothesis as described above: Judge the child, do specific blood tests, and based on evidence provided, stick to doses at the upper end of the THERAPEUTIC DOSE as recommended by Drugs Controller of India or WHO for micronutrients that demand it, and provide only recommended PROPHYLACTIC DOSES of other micronutrients, spacing them between the four meals in compatible groups in a day to avoid drug-to-drug interactions.

Only data that is open to parental scrutiny is given below. Certain Specifics of the study are copyright material, and is meant only for the Investigators, Ethics Committee and Drugs Controller of INDIA, and hence deleted from the write-up below.

Chief Investigator

Co-Investigators

Dr. I C Verma, FRCP, FAAP, FAMS
Sr. Consultant & Chairman, Dept. of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi

OBJECTIVE

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 subsidized cost.
• 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 (1^st, 2^nd, 3^rd or 4^th), 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

1. 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.
2. Supplemental Therapies

1. Standard Therapy
   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

6. Assessments
   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.

PARAMETERS

This study is designed to investigate early medical interventions using MB12 in otherwise healthy children with autism in India

Medical Interventions proposed

1. 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.

1. 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
2. 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.
3. 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.
4. 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.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Procedure:

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.

Tolerance:

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.

Analysis:

The data will be analyzed using standard statistical methods to assess the benefit to risk ratio of each phase.

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 [__]

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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