DOUBLE BLIND PLACEBO CONTROLLED RANDOMISED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF VITAMIN MB12 AND CHELATION OF EXCESSIVE HEAVY METAL IN BODY FOR REDUCING SEVERITY OF AUTISM IN AFFECTED CHILDREN

(in addition to Standard Therapies, GFCF Diet, DAN Protocol based Biochemical approach, mHBOT)

GET THE BASICS RIGHT FIRST

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 children respond to 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 biochemicaal 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 rarely 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.

Current Status:

1. Protocol and Proforma: Ready
2. Drugs (Vitamin Methyl B 12: 25 mg/ml), Equipments, Center, Staff selection: Ready
3. Permission of Regulatory Authorities: On the job. Pending as of 24/12/2009

Last updated on December 24, 2009

Chief Investigator

Co-Investigators

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

Dr. (Ms.) M S Ray, MD
Sr. Consultant in Pediatrics, Majeedia Hospitalm Hamdard University, New Delhi

IMPORTANT NOTE

We applied to Drugs Controller of India (DCI) for permission to start a double blind placebo controlled randomised study of vitamin Methyl B12 injection (25 mg/ml formulation) in children with autism. That was more than 150 days ago as on this date. We are still awaiting his kind consideration and written permission to start the study.

It is and will remain the single minded pursuit of FSMHP-UDAAN to help children with Autism. If anyone out there can help, please do, and not for us but for the nearly quarter million or more children with Autism Spectrum Disorder in India

This first in the world study in this manner can only start after mandatory clearance by DCI, followed by ICMR Registration and Ethics Committee approval.

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 drug is likely to be supplied to selected 100 children only, at subsidized cost.
• We are negotiating with all labs to get all tests done at discount (Typically 20 to 25%). The facility for discount can be extended to all children who get them clinically assessed at UDAAN-INDIRA, whether or not part of the study.
• The children selected for the study will have to come at a pre-designated week (1^st, 2^nd, 3^rd or 4th), once in 3 months, for 6 working days (Monday morning 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. No child who is excluded from the study will have 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 in New Delhi of Religare (formerly SRL Ranbaxy Labs) or Dr. Lal’s Central Clinical Lab or Genetics Dept of Sir Ganga Ram Hospital or DIFI (for CT-cum-SPECT Fusion Scan of brain prior to HBOT if being done). No tests done anywhere else are acceptable as per our research protocol as submitted to Drugs Controller of India. This even excludes branches of these same labs elsewhere in Delhi or any other city.
• 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, Pediatrician’s checkup, Internists assessment 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.
• After the 12 month study period, (start of humanitarian treatment phase), every child randomly allocated to the Placebo group, will receive the actual MB12 and DMPS for the full course at the same subsidized cost for tests, evaluations and drugs (Cost of drugs as charged during placebo phase will be adjusted during this phase).
• In the fourth (humanitarian treatment) phase, parents who wish may avail of mHBOT at UDAAN-INDIRA, subject to availability of slots, at a subsidized rate of Rs.1000 (As per current cost, subject to revision as per market forces beyond our control) per single session of 1.3 ATA ambient air 1.5 hours at a time. High pressure 100% Oxygen HBOT is available at Apollo Hospital, subject to availability of slots, but at just about double the cost.
• Parents opting for Standard Therapy at our premises, especially during the mHBOT phase, may be given the facility subject to availability of free time slots and therapists.

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. Trial Stage I:
   100 Children aged less than five years, with proven ASD as per DSM-IV, CARS, VABS, and other tests as appropriate, will be randomized into two batches as per flow chart above. One batch will receive MB12 while the other will receive matching placebo injections. Evaluation will be repeated at month 3 and 6.
3. Trial Stage II (Proposed. DCI permission to be obtained):
   Each child will undergo heavy metal testing (mercury by urine challenge testing and blood tests for arsenic, lead, cadmium, aluminum). Every child, who shows heavy metal toxic levels in body, irrespective of batch, will get heavy metal detoxification while continuing the same injection as before. Repeat blood tests and evaluations will be done at month 9 and 12, and the Trial concluded thereafter.
4. Post-trial Humanitarian Continuation Phase: The Drug Codes will now be revealed and each child will get MB12 for total 24 weeks and each heavy metal overloaded child will get oral detoxification therapy for at least 18 months. Blood tests at designated Labs at Delhi are Mandatory under our supervision after detailed assessment at our center, in the same week every three months in order to receive the test drugs.
5. Supplemental Therapies

1. Standard Therapy
   Intensive Sensory Integration Therapy, Special Education, Speech Therapy, Occupational Therapy, etc, will be provided to all children, as per laid down Standard Therapy protocols followed in all Autism management centers
2. Low Pressure Hyperbaric Air Therapy
   During the Post-Trial Humanitarian Continuation Phase, parents desirous of mHBOT, will have their child tested by CT-SPECT Fusion Scan of Brain to asses the functional status of oxygen perfusion. Children who have definite evidence of anoxic brain lesions, especially in the Temporal Lobe, Basal Ganglia and Cerebellum, will receive Low Pressure Hyperbaric Air (HBA) therapy for 20 days, followed by a gap of 2 months, for repeat cycles of HBA therapy for a total of 100 sessions. Parents wanting to try high pressure 100% Oxygen HBOT will have to try their luck with the limited slots available at Apollo hospital, at twice the cost of mHBOT.

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 some of the need-based early medical interventions for 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, a concentrated formulation of Vitamin MB12 (25 mg/ml) 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.

Mild pressure Hyperbaric Air Therapy

Post Trial Therapy by choice

1. Replacement of normal metals by mercury to produce immunogenic chemicals, abnormal immune state and deficiency of Glutathione: all contribute to an enhanced state of inflammatory edema in the brain of autistic children, resulting in a brain size generally larger than an age, sex and weight matched normal child.
2. Studies at Virginia University by Dr. Dan Rossignol and other centers in US have shown that if children with autism are first managed to improve their general health, restore vitamin MB12 levels, and treatment initiated to remove absorbed / ingested mercury, then, follow up low pressure Hyperbaric Therapy may help reduce brain edema, restore microcirculation and restore normal brain activity much faster. Such therapy is available in India and was pioneered by UDAAN.
3. In a recent study published in BMC, Rossignol et al showed in a randomized double blind placebo controlled study in children with autism treated with 1.01 ATA (normal atmosphere) Vs. 1.3 ATA (compressed ambient air) that Hyperbaric air therapy was statistically significantly useful means to reduce the severity of symptoms and signs of autism.

Inclusion Criteria:

• Children provisionally diagnosed as Autism, attending the OPDs of Majeedia Hospital, Sir Ganga Ram Hospital Genetics OPD or UDAAN - INDIRA Center, or other legally 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 25% concession), 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 - INDIRA.

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 or DMPS oral capsules.

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 proforma enclosed. The children will also be assessed clinically for Cognitive parameters using internationally approved scales (CARS, VABS, Sensory Profile, 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.

In addition, this study will attempt to see which early medical interventions help an Indian autistic child in the Indian setting, to improve his/her quality of life, cognitive skills, psycho-social skills, communication ability and general behavior.

To identify the role of each intervention, only one intervention will be initiated at a time, and the effects observed for six months before initiating the next intervention

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, DMPS chelation and hyperbaric therapy also.

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.

Mild pressure Hyperbaric Air Therapy is known to rarely cause relapse of fits. In such cases, further mHBAT may be temporarily withdrawn or reconsidered.

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: _____________________________________