Dr. Arun Mukherjee, MD
Sr. Consultant in Medicine, Majeedia Hospital, Hamdard University, New Delhi
Director, FSMHP-UDAAN Autism Project, C/27-28 Dayanand Colony, New Delhi-24
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.
PROPOSED PROTOCOL (Subject to revision as per DCI orders)
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 (1st, 2nd, 3rd 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.
The objective of this study is to evaluate relevant and available biochemical and errors of metabolism profile of children with autism, and then try to improve their developmental standards and quality of life in phases of intervention as mentioned above. They MUST continue Standard Therapies, if any, as before.
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.
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.
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.
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.
Supplemental Therapies
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
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.
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
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, 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.
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.
Mercury and toxic heavy metal Chelation Therapy (This phase postponed for now: See top of page)
Mercury poisoning resembles Autism in many aspects.
Mercury and other toxic heavy metals have contaminated our ground water and food chain, due to rapid industrialization and discharge of chemical effluents into our rivers, lakes, ponds and land-fill sites. Fossil fuels burning, use of heavy metal based colors, chemicals, food additives and many drugs including Thiomerosal preservative in many multidose injection vials could contribute to overload susceptible children into developing symptoms of Autism Spectrum disorder. The Epidemiological studies in US, using the VAERS Database, have shown that there may be a possibility that mercury in Thimerosal preservative used in multidose vaccine vials may have neurological adverse effects in some children (1 in 166), due to genetic inability to excrete mercury and other heavy metals efficiently.
Further papers have also highlighted the additional contribution to Neuro-toxicity by Lead, Cadmium, Aluminum, Copper and Arsenic.
In future, after permission from requisite regulatory authorities, we will also be studying the levels of these neuro-toxic chemicals and their control by heavy metal removal therapies as outlined above.
Routine tests for mercury in blood, urine, hair or stool often draw a blank because the metal is removed from blood rapidly and gets incorporated into intracellular chemicals, especially in
brain, displacing normal metal ions like zinc from intracellular proteins and enzymes.
Mercury accumulation can be detected by collecting an overnight urine sample, then giving the child 10 mg/kg oral DMPS (2,3-dimercapto-1-propanesulfonic acid:- a relatively safe and effective mercury chelating agent), and collect the next 12 hours urine separately. An enhancement in mercury excretion by 3 fold or more in the second sample is diagnostic of mercury poisoning.
Children showing evidence of mercury or other toxic heavy metal poisoning, will receive DMPS capsules at appropriate dosage for 3 days, then gap of 11 days, repeated for 2 years or till
urine challenge tests become negative.
Mild pressure Hyperbaric Air Therapy
Post Trial Therapy by choice
Hyperbaric Therapy refers to the placement of a patient inside a
pressurized chamber for some time, to enhance the solubility of oxygen in
the intra-vascular and extra-vascular water content, as per Henry’s
Law of Physics. This enhances the diffusion of oxygen enriched tissue
fluid into an ischemic zone from the surrounding normally perfused areas. Research by Wassman
et al in Germany
has shown that the optimum pressure for such a beneficial activity is 1.3
to 1.75 atmospheric pressure absolute (ATA). The
optimum and safe time limit of such a therapy has also been worked out as
one session a day, with 60 minutes at target pressure, for not more than
40 sessions at a stretch.
Hyperbaric therapy of brain lesions has shown reductions in size of
dysfunctional ischemic zones, stimulation of stem cell activity, reduction
of edema, enhancement of capillary circulation, enhancement of neo-vascularisation, and augmentation of Neuro-plasticity.
These lead to a significant degree and a faster onset, of brain function
revival. The basis of mild hyperbaric therapy is as follows:
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.
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.
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.
PROFORMA
(DELETED AS CONFIDENTIAL)
INFORMED CONSENT
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)
I confirm that I have read and understood the information sheet attached, for the above study and have had the opportunity to ask questions.
[_]
(ii)
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.
[_]
(iii)
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.
[_]
(iv)
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)
[_]
(v)
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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