Ambroxol Trial Results

[Bolt_Upright]

Am I reading the Ambroxol trial results correctly on page 32? They don't seem to be showing improvement over time. Some a little better, some a little worse?

cdn.jamanetwork.com/ama/con...

[park_bear]

At the end of the 186 day treatment period there was a seven point improvement in UPDRS part III. However, 90 days after cessation of treatment, that improvement was lost as scores reverted to pretreatment values.

Good for you for checking this auxiliary information!

[Bolt_Upright in reply to park_bear]

Now I see that UPDRS Part 3 shows about a 6 point improvement. Still odd that Parts 1, 2, and 4 don't pull that down to about a 1.7 point improvement. But I will trust their total.

Based on looking over the UPDRS test, part 3 is all about movement, so that seems to be where the benefit was?

movementdisorders.org/MDS-F...

PLEASE NOBODY READ MY WORDS AND THINK I KNOW WHAT I AM TALKING ABOUT.

[park_bear in reply to Bolt_Upright]

Yes part three is all about movement.

[Bolt_Upright in reply to park_bear]

FYI I added to this post. I did not put it here as I did not want to seem like I was replying to you (because I was not, and you are nice, and I was replying to Ambroxol). Thanks for the clarifications.

[Hidden in reply to Bolt_Upright]

We are all laymen. No need to keep warning us. Truly.

[Bolt_Upright in reply to Hidden]

Thanks CC. My concern is somebody that is desperate, like a lot of us are, will jump on some plan of mine like it will save their lives. And my plans are not even mainstream alternative plans. I started my Zeolite Clinoptilolite today (and not that super expensive liquid form (and not that super cheap powder that has not been micronized (I got some Zeolite Pure))).

[Bolt_Upright]

So... the Ambroxol trial had 17 people in it, went for 6 months, had a 6 point reduction in UPDRS III taking over 1000 mg of cough medicine. Costs $4 or $5 a day to get.

The Niacin trial had 41 people, went for a year, and had a 3.5 point reduction in 12 months. If you factor in the expected 5.5 UPDRS decline over the year, the improvement is 9 points. Niacin is cheap and available.

Reviewing some evidence:

scienceofparkinsons.com/202...

Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate

onlinelibrary.wiley.com/doi...

So they were giving 100 mg of Ambroxol to about a 4 pound Cynomolgus monkey to get the GCase activity going in the brain. 22.5 mg did nothing for the GCase in the brain. The whole study is based on one monkey from what I can tell. So I weigh 170 lbs. I weigh 42 times more than the monkey so I would need 4200 mg of Ambroxol? I'm not seeing the evidence for spending $170 a month and popping 20 to 40 pills a day.

I am not a smart man, but I'm thinking I will take a flyer on Ambroxol at 90 mg a day. I like the GCase washing machine concept. I'll either spread them out or maybe take all 3 at once so it can punch its way into my brain. And I will keep up the niacin (and butyrate during the time niacin is out of my body. They both bind to the GPR109A receptor, which is anti-inflammatory).

I edited some of the Niacin study to make it more succinct and easier to read. I don't think I skewed anything:

researchgate.net/publicatio...

Primary Outcome: UPDRS III

A decreased average score of 3.5 ±6 points (indicating an improvement) in the UPDRS III score was observed after 12 months of daily niacin, from 21.5 ±12.9 to 17.7 ±11.7 points, t(41) = 3.6.

The reversal in symptoms observed in this study represents an average improvement of 9 ±6 points (−16%) in the UPDRS III based on the expected 5.5-point decline minus

the observed −3.5-point improvement.

Inclusion of the four subjects who dropped out of the 12-month intervention produced the same results: UPDRS III improved from 21.5 ±12.9 to 18.1 ±13.0 points, t(45) = 3.9, representing an overall 9 ±6-point swing in score.

There was no association between the UPDRS score at baseline or 12 months and disease severity, duration of disease, or carbidopa intake.

Secondary Outcomes/Clinical Measures

Many secondary outcome measures also improved. Particularly,handwriting size increased, perception of fatigue decreased, mood improved, frontal beta rhythm during quiet stance increased, and stance postural control improved.

Set shifting as inferred from the Trail Making Test worsened from 66 to 96 s.

Other measures did not change after 12 months, but it is not clear whether this represents a positive benefit of the vitamin. For example, while the quality of night sleep remained the same at 79% efficiency ±14 and 15, respectively (p= 0.47), there was a weak trend and small effect towards a 10% decrease in the average frequency of awakening episodes, from 8 to 7 times nightly.

[kevowpd in reply to Bolt_Upright]

Neither of those trials had placebo cohorts. This is significant regarding any measured improvement in the PWP involved.

[Bolt_Upright in reply to kevowpd]

Very true kevowpd. This stuff is hard to sort out and you can only try so many things.

[kevowpd in reply to Bolt_Upright]

Or so it seemed until you appeared 😂

[Gioc in reply to kevowpd]

No, Everyone knows that the use of placebos in research on vitamins, such as niacin, which are not drugs, is limited.

[Hidden in reply to Bolt_Upright]

I take B3/Niacin as well as Ambroxol, B12, D, etc, etc. anything available to me now that I can reasonably take to slow my progression that I believe works. Having PDD is not a place I want to be in 5-10 years, or any number of years. I've seen firsthand what that looks like.

[pmmargo in reply to Hidden]

amen! I think it is important to try to find out your phenotype first. And focus on what the best treatments are for that phenotype. Unfortunately parkinsons like schizophrenia and lupus are very diverse in symptoms and may not be a single disease.

[LAJ12345 in reply to Bolt_Upright]

I think each supplement does different things so you can’t compare 2 treatments that improve things by the same amount. Who knows, together they might improve things twice as much or more if they are synergistic.

[park_bear in reply to Bolt_Upright]

The "expected 5.5-point decline" they state for the part three UPDRS in the niacin trial is wrong. If true that would mean Parkinson's patients would in general go from slight symptoms to maximum severe for every motor symptom in about 10 years. Not true. Even if it were true we should then also add those same 5.5 points to the results of every substance tested for Parkinson's, but we do not, so what they are claiming is an unfair advantage.

In any case the correct comparison would be against a placebo group, which would suffer the adverse effect of progression in addition to the psychological boost of believing they were treated. In table 2 of the study they show a valid three month trial in which the placebo patients improved by two points, the 100 milligram niacin patients improved by 4.5 points, and the 250 milligram niacin patients got worse by one point. The ensuing twelve-month trial without a placebo group is much lower evidential value - because no placebo comparison.

[Bolt_Upright in reply to park_bear]

Great point on the apple and oranges factoring in a decline park_bear.

Also on the fact that the 250 mg group actually got worse over 3 months. I found this in the report that I think relates and is interesting. It seems the 250 mg group's nicain levels DROPPED over the first 3 months:

Biochemical Measures

Niacin Plasma Levels

The interaction effect in the two-way Time ×Group mixed ANOVA was significant, F(4,65) = 4.84, p= 0.0018. Tukey’s simple effect analyses on each group showed that niacin levels decreased at 3 months for the 250-mg group only (p<0.0001). At 12 months, niacin levels increased across the groups by an average of 34% compared to those at baseline, p<0.0001, ES = 1.2 (Figure 2)

Also, I could not read table 2 on my browser. It was just too small so I pulled an image of it and am adding it here.

Niacin Report Table 2

[pmmargo in reply to Bolt_Upright]

I believe ambroxyl is supposed to work for those with GBA gene mutations, but not in general. Many trails are treating Parkinsons as a homogenous group while in fact there are known to be phenotypes.

[Hidden]

As I understand the trial report, it was for 6 months (186 days) during which time 18 participants took Ambroxol as below, but they measured 7 of them again at 9 months (279 days), three months after it had ended, during which time I don't believe they were still taking it:

"6.3 Study Duration Each participant will receive 5 intra-participant dose escalations at 60 mg TID (day 1-7), 120 mg TID (day 8-14), 180 mg TID (day 15-21), 300 mg TID (day 22-28) and 420 mg TID (day 29-186) for the duration of 6 months and will be followed up for 9 months from administration of the first dose of ambroxol at day 1."

Trial 'exploratory' objectives included measuring Parkinsons cognitive performance score changes as below over that period at intervals of 1 (29 days), 3 (93 days), 6 (186 days), and 9 (279 days) months:

"4.3 Exploratory Objective: To explore whether ambroxol leads to improvement in cognitive performance, Montreal Cognitive Assessment (MoCA) and the motor and non-motor features of Parkinson disease from day 1 to day 186. To explore whether ambroxol leads to improvement in Parkinson Disease non-motor symptom assessment scale (NMSS) and non-motor symptom questionnaire (NMSQuest) from day 1 to day 186."

cdn.jamanetwork.com/ama/con...

In the abstract summary, the researchers focus in on Part III Movement Examination of the MDS-UPDRS (movementdisorders.org/MDS-F..., and cite this result through 6 months (186 days):

"Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, –10.4 to –3.1; P = .001). These changes were observed in patients with and without GBA1 mutations."

jamanetwork.com/journals/ja...

This statement corresponds with the results noted in the trial table on page 32 you reference:

Movement disorders Society Unified Parkinson disease rating scale (MDS UPDRS) part III

Baseline Day 29 Day 93 Day 186 Day 279 (washout)

All 31.1 (14.5) 27.2 (10.7) 24.3 (12.1) 31.9 (12.7)

GBA1 38.4 (15.9) 31.5 (11.1) 30.3 (13.1) 37.4 (11.4)

non GBA1 24.3 (9.6) 23.7 (9.5) 19.0 (8.7) 27.5 (12.4)

cdn.jamanetwork.com/ama/con...

On a combined 'All' basis the score decreased (improved) by 6.8 (31.1-24.3) points from Day 1 to Day 186 (6 months), and thereafter when they had stopped taking it for 3 months it increased (worsened). This pattern was true for both the GBA1 and non-GBA1 groups, but the non-GBA1 group benefited slightly less and worsened more after they stopped taking it than the GBA1 group. Given the sample size measured at 279 days ( 9 months) was only 6 of the 17 measured (18 less 1 for blood-contamination) at 186 days (6 months), I'm not sure we can read much into this higher worsening of the non-GBA1 group after they stopped taking it. The trial currently underway and coming out sometime next year should have a lot more such score data in its review.

It would appear the Part III score was highlighted as it had the most significant change and is "the most common functional endpoint used in PD trials but it has limited sensitivity to change in early PD." mdsabstracts.org/abstract/i... The participants in this trial had "moderate PD" and were at "stage 3 or less", not early stage. The parts I, II & IV scores in the table are indeed a mixed bag of results, but they do not appear to be clinically significant based on this study ( pubmed.ncbi.nlm.nih.gov/301..., except for perhaps the Part IV non-GBA1 which improved more than the minimally significant .9 range. (As for the other measures - MoCa, NMSS, NMSQuest - when I have more time I will take a closer look at them as well). Thanks for asking me to dig into them, it was worth the trip!

PS, to your safety question, this was in the more detailed report:

"To date, ambroxol has been used as an over-the-counter cough linctus for peripheral effects on respiratory mucosa. It has obtained market authorisations in a number of European markets. It has been shown in a number of studies to be safe for long term administration (Narita et al., 2016 & Zimran et al., 2013). This includes the study of Narita et al., 2016 where participants were given ambroxol in excess (up to 1.3 g total daily dose) of the maximum dose of 1.26g total daily dose proposed in our protocol, and for periods of up to 4 years. A number of other studies have used a total daily dose in excess of 1g for up to 10 days including one in the third trimester of pregnancy (Wu et al., 2014 & Baranwal et al., 2015)...We have reviewed the above animal, non-human primate and patient data and selected the 1260 mg/day dose to ensure efficacy in target engagement in the CNS, and detection in the CSF. The data indicate that a lower dose may not penetrate the CNS, or induce an effect necessary to enhance glucocerebrosidase activity."

[Bolt_Upright in reply to Hidden]

Well done! So I see that the MoCa scores all improved by a little more than a point. That's a good thing!

[Raphaekg]

This is a phase 1 safety study. It is simply intended to determine whether there was CSF increase in Ambroxol and to examine drug safety. The change in UPDRS should not be given much credence. The full text states, "Interpretation of the changes in MDS-UPDRS and MoCA results is difficult in the context of a nonplacebo-controlled study."

These results justify the next step: a randomized, controlled clinical trial (Phase 2 study) with placebo contrast group. The uncontrolled Phase 1 safety study is standard practice with new pharmacotherapy interventions, to show safety and target engagement.

[Bolt_Upright in reply to Raphaekg]

Thanks Raphaekg, well stated. You know, I started wondering last night: Is it a good thing to have more a synuclein in your CSF? (The things I get to wonder about nowadays. It used to be "Should the Brown's resign Baker Mayfield?, and now it is all about a synuclein).

[LAJ12345]

We decided to go slow on the ambroxol due to hubby’s over reaction to any drugs so he is just taking 2x 30mg twice a day. He also started 2 tsp of cinnamon a day at the same time over the last 2 weeks.

He has definitely been feeling much better, and laughing, being more proactive, less apathetic.

He has also finally come off the last tiny amount of mirtazapine and sertraline 6 weeks ago that he has been weaning off for years. So tiny you wouldn’t think it would have any impact but who knows. They certainly made him considerably worse when he went on them.

(He also takes niacin in Hardys daily essential nutrients with added vitamers)

[Bolt_Upright in reply to LAJ12345]

2x30 twice a day for Ambroxol. That's an interesting dose. Thanks for sharing.

[LAJ12345 in reply to Bolt_Upright]

It is the max dose on the packet. As hubby is an over reactor to pharmaceuticals, ie he has every side effect of almost any medication he takes, I like to err on the side of caution. Eg with mirtazapine the prescription was 30mg. He ended up reducing it to 1 mg (he is now off it due to side effects)

His genetic profile shows he is slow to process pharmaceuticals in his liver.

[bullet65]

I was a participant in the Ambroxol trial in London Ontario. It was a double blind phase 2 trial. The trial lasted for 12 months and a possible 6 month extension. For the first 12 months I noticed little or no improvement. I presumed that I might be getting the placebo and opted for the 6 month extension in which I was guaranteed to be getting Ambroxol. In my experience Ambroxol has little to no effect on dementia or motor skill improvement. Everyone is different and results may vary but I don't recommend high dose Ambroxol for the treatment of PD.

[Bolt_Upright in reply to bullet65]

Thank you for sharing. It is much appreciated.

[Bolt_Upright in reply to bullet65]

So do you think maybe the Ambroxol stopped progression during the 6 months you knew you were on it? I am just thinking improvement might be more challenging than stopping or slowing progression.

[Hidden in reply to bullet65]

“Noticed little or no improvement.” I truly thought the goal of Ambroxol was just to not get worse.

May I ask, do you think your PD got worse while on Ambroxol?