Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans
Abstract
:1. Introduction
2. Results
2.1. Search and Selection
2.2. Critical Appraisal Assessment
2.3. Patient Characteristics and Treatment Modalities in Selected Studies
2.4. Safety Assessment and Adverse Events Reported in Selected Studies
2.5. Relatedness of Adverse Events to the Study Drug in Selected Studies
2.6. Efficacy Assessment from Selected Studies
2.7. Influence of the Administration Route and Size of the Effect
3. Discussion
3.1. Safety and Efficacy of Neurotrophic Therapies of Degenerative Disorders
3.2. Translation from Animal Studies to Human Trials
3.3. Applicability of NF Therapies to the Auditory Nerve
4. Methods
4.1. Search Strategy and Study Selection
4.2. Quality Assessment of Selected Study
4.3. Data Extraction
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Appendix A
Database | Syntax | |
---|---|---|
Medline | 1 | Exp Nerve Growth Factors/ |
2 | (BDNF or (brain adj3 (neurotrophic* or neuro trophic* or neurotropic* or neuro tropic*))).tw. | |
3 | (NGF or ((nerve or neurotropic* or neuro tropic* or neurotrophi* or neuro trophi* or neuronotrophi* or neurono trophi* or neurite*) adj3 (outgrowth or growth or factor*)).tw. | |
4 | 1 or 2 or 3 | |
5 | Animals/ not (Animals/ and Humans/) | |
6 | 4 not 5 | |
7 | Exp In Vitro Techniques/ | |
8 | “in vitro”.ti. | |
9 | 7 or 8 | |
10 | 6 not 9 | |
11 | Limit 10 to yr=”1995-Current” | |
12 | Limit 11 to clinical trial, all | |
Embase | Modeled search strategy for Medline, in title/abstract | |
Cochrane | Modeled search strategy for Cochrane, in title/abstract | |
Global health | Modeled search strategy for Global Health, in title/abstract |
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Study | Directness of Evidence (DoE) | DoE Score | Risk of Bias (RoB) | RoB Score | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Publication Year | Study Design | Indication for Treatment | Demographic Data | Treatment Approach | Efficacy Outcome Measures | Safety Assessment | Follow-Up | Randomization | Blinding | Standardization (T) | Standardization (O) | Standardization (FU) | Missing Data | |||
Cedarbaum et al. [39] | 1995 | RCT | ● | ◑ | ● | ○ | ● | ◑ | M | ● | ● | ◑ | ● | ● | ● | L |
Cedarbaum [27] | 1996 | RCT | ● | ◑ | ● | ● | ◑ | ● | H | ● | ● | ○ | ● | ● | ● | L |
Miller et al. [40] | 1996a | RCT | ● | ◑ | ● | ○ | ● | ◑ | M | ● | ◑ | ◑ | ● | ● | ● | L |
Miller et al. [28] | 1996b | RCT | ● | ◑ | ● | ● | ● | ◑ | H | ● | ◑ | ◑ | ● | ● | ● | L |
Lai et al. [38] | 1997 | RCT | ● | ◑ | ● | ● | ● | ○ | M | ● | ● | ● | ● | ● | ● | L |
Apfel et al. [48] | 1998 | RCT | ● | ◑ | ● | ● | ● | ◑ | H | ● | ● | ◑ | ● | ● | ◑ | L |
Borasia et al. [35] | 1998 | RCT | ● | ○ | ● | ● | ◑ | ◑ | M | ● | ● | ● | ● | ● | ● | L |
Apfel et al. [44] | 2000 | RCT | ● | ◑ | ● | ● | ● | ○ | M | ● | ● | ● | ● | ● | ● | L |
Bensa et al. [37] | 2000 | RCT | ● | ● | ● | ○ | ● | ○ | M | ● | ● | ● | ● | ● | ◑ | L |
Ochs et al. [41] | 2000 | RCT | ● | ◑ | ● | ○ | ● | ◑ | M | ● | ● | ○ | ● | ● | ● | L |
Wellmer et al. [45] | 2001 | RCT | ● | ◑ | ● | ● | ● | ◑ | H | ● | ● | ◑ | ● | ● | ◑ | L |
Ettinger et al. [49] | 2003 | RCT | ● | ◑ | ● | ● | ● | ● | H | ● | ● | ◑ | ● | ● | ● | L |
Nutt et al. [31] | 2003 | RCT | ● | ◑ | ● | ● | ● | ◑ | H | ● | ● | ◑ | ● | ● | ◑ | L |
Landi et al. [36] | 2003 | RCT | ● | ● | ● | ● | ○ | ● | H | ● | ● | ● | ● | ● | ● | L |
Lang et al. [42] | 2006 | RCT | ● | ◑ | ● | ● | ● | ◑ | H | ● | ● | ● | ● | ● | ● | L |
Sorenson et al. [43] | 2008 | RCT | ● | ◑ | ● | ● | ● | ● | H | ● | ● | ● | ● | ● | ● | L |
Zhang et al. [50] | 2011 | RCT | ● | ◑ | ● | ● | ● | ○ | M | ● | ● | ◑ | ● | ● | ● | L |
Birch et al. [47] | 2013 | RCT | ● | ◑ | ● | ● | ● | ● | H | ● | ◑ | ◑ | ● | ● | ● | L |
Nakagawa et al. [51] | 2014 | RCT | ● | ◑ | ● | ● | ● | ● | H | ● | ● | ● | ● | ● | ◑ | L |
Rolan et al. [46] | 2015 | RCT | ● | ◑ | ● | ● | ● | ● | H | ● | ● | ◑ | ● | ● | ● | L |
Valk et al. | 1996 | RCT | ● | ◑ | ● | ● | ○ | ● | M | ● | ● | ◑ | ● | ● | ○ | M |
Lambiase et al. | 1998 | CT | ● | ● | ● | ● | ○ | ● | H | ○ | ○ | ◑ | ● | ● | ● | H |
Bonini et al. | 2000 | CT | ● | ◑ | ● | ● | ○ | ● | M | ○ | ○ | ● | ● | ● | ● | M |
Parkman et al. | 2003 | RCT | ● | ◑ | ● | ● | ● | ○ | M | ● | ● | ○ | ● | ● | ◑ | M |
Gill et al. [29] | 2003 | PCS | ● | ● | ● | ● | ● | ● | H | ○ | ○ | ○ | ● | ● | ● | H |
Patel et al. [30] | 2005 | |||||||||||||||
Beck et al. | 2005 | RCT | ● | ◑ | ● | ● | ○ | ○ | L | ● | ● | ◑ | ● | ● | ○ | M |
Tuszynski et al. | 2005 | CT | ● | ◑ | ● | ● | ○ | ● | M | ○ | ○ | ● | ● | ● | ◑ | H |
Slevin et al. | 2005 | PCS | ● | ● | ● | ● | ● | ● | H | ○ | ○ | ◑ | ● | ● | ● | H |
Slevin et al. | 2006 | |||||||||||||||
Slevin et al. | 2007 | |||||||||||||||
Nguyen et al. | 2006 | RCT | ● | ◑ | ● | ○ | ● | ◑ | M | ● | ○ | ◑ | ● | ● | ● | M |
Sieving et al. | 2006 | PCS | ● | ◑ | ● | ● | ● | ● | H | ○ | ○ | ● | ● | ● | ○ | H |
Marks et al. | 2008 | CT | ● | ● | ● | ● | ● | ● | H | ○ | ○ | ◑ | ● | ● | ● | H |
Nguyen et al. | 2009 | RCT | ● | ◑ | ● | ○ | ● | ● | M | ● | ○ | ◑ | ● | ● | ● | M |
Zhou et al. | 2009 | RCT | ● | ○ | ● | ● | ○ | ◑ | L | ● | ○ | ○ | ● | ● | ● | M |
Sacca et al. | 2011 | RCT | ● | ◑ | ● | ● | ● | ○ | M | ● | ● | ○ | ● | ● | ◑ | M |
Zein et al. | 2014 | CT | ● | ● | ● | ● | ● | ● | H | ○ | ○ | ● | ● | ● | ◑ | H |
Chew et al. | 2015 | CT | ● | ◑ | ● | ● | ● | ● | H | ○ | ○ | ◑ | ● | ● | ● | H |
Tan et al. | 2015 | CT | ● | ● | ● | ● | ○ | ○ | M | ○ | ○ | ◑ | ● | ● | ● | H |
Directness of Evidence (DoE) | |
---|---|
Study design | CT, clinical trial PCS, prospective case series RCS, retrospective case series RCT, randomized control trial |
Indication for treatment Diagnosis | Clearly reported, ● Not clearly reported, ○ |
Demographic data Age at treatment | Individually reported, ● Means reported, ◑ Not reported, ○ |
Treatment approach NF used, dosage, route of administration | Reported, ● Not reported, ○ |
Efficacy outcome measures Pre and post treatment assessment | Reported, ● Not reported, ○ |
Safety assessment Quantifiable adverse events per patient If drug was attributed to reported adverse events | Reported per patient or per event, ● Events reported but not quantified, ◑ Not reported, ○ |
Follow-up Duration of follow-up at the end of treatment for all tested individuals | ˃2 months, ● <2 months, ◑ not reported, ○ |
Overall DoE score | High, ≥5 points Moderate, between 4–5 points Low, <4 |
Risk of Bias (RoB) | |
Randomization | Randomized or concealed, ● Not randomized or concealed, ○ |
Blinding | Blinding of patient, researcher, observer, ● Single blind, ◑ No blinding, ○ |
Standardization of treatment | All patients received the same therapy, ● Different types of NFs or dosage used, ◑ Dosage modified throughout trial, ○ |
Standardization of outcome measures | Identical outcome reports, ● Reported however not standardized, ◑ Not reported, ○ |
Standardization of follow up | Identical follow up for all patients, ● Reported however not standardized, ◑ Not reported, ○ |
Missing data | No missing data; missing data mentioned/quantified and Method of handling described, ● Missing data mentioned in study but method of handling Not described, ◑ Missing data not reported, ○ |
Overall RoB score | Low, ≥5 points Moderate, between 4–5 points High, <4 |
Study | Diagnosis | Total pts (NF Group) | NF | Dose | Administration | Safety Conclusion | Efficacy Conclusion |
---|---|---|---|---|---|---|---|
Cedarbaum et al. (1995) [39] | ALS | 57 (43) | CNTF | 0.5, 1, 3, 7, 10, 30 µg/kg | Thrice weekly s/c injection per week for 2 weeks | Safe | N/A |
Cedarbaum et al. (1996) [27] | ALS | 730 (485) | CNTF | 15, 30 µg/kg | Thrice weekly s/c injection per week for 9 months | Not safe | Not effective |
Miller et al. (1996b) [28] | ALS | 44 (33) | CNTF | 0.5, 2, 5, 10, 20 µg/kg | Thrice weekly s/c injection for 1 month | Safe (0.5, 2, and 5 µg/kg) | N/A |
Miller et al. (1996a) [40] | ALS | 483 (360) | CNTF | 0.5, 2, 5 µg/kg | Daily s/c injection for 6 months | Safe | Not effective |
Lai et al. (1997) [38] | ALS | 266 (176) | IGF-I | 0.05, 0.1 mg/kg | Twice daily s/c injection for 9 months | Safe | Effective |
Apfel et al. (1998) [48] | Diabetic polyneuropathy | 250 (168) | NGF | 0.1, 0.3 μg/kg | Thrice weekly s/c injection per week for 6 months | Safe | Effective |
Borasio et al. (1998) [35] | ALS | 183 (124) | IGF-I | 0.10 mg/kg | Daily s/c injection for 9 months | Safe | Not effective |
Apfel et al. (2000) [44] | Diabetic polyneuropathy | 836 (394) | NGF | 0.1 μg/kg | Thrice weekly s/c injection per week for 12 months | Safe | Not effective |
Bensa et al. (2000) [37] | Guillain–Barre syndrome | 10 (6) | BDNF | 25 µg/kg | Daily s/c injection for a maximum of 6 months | Safe | Not effective |
Ochs et al. (2000) [41] | ALS | 25 (20) | BDNF | 25, 60, 150, 400, 1000 µg/kg | Daily intrathecal delivery for 3 months | Safe (25, 60, 150 µg/day) | N/A |
Wellmer et al. (2001) [45] | Diabetic polyneuropathy | 27 (19) | BDNF | 25, 100 µg/kg | Daily s/c injection for 3 months | Safe | Not effective |
Nutt et al. (2003) [31] | PD | 50 (38) | GDNF | 150, 361, 559, 1588, 3311 µg | ICV for 8 months | Not safe | Not effective |
Ettinger et al. (2003) [49] | Obesity | 173 (141) | CNTF | 0.3,1, 2 µg/kg | Daily s/c injection for 2–3 months | Safe (0.3, 1 µg/kg) | Effective |
Landi et al. (2003) [36] | Pressure ulcer of the foot | 36 (18) | NGF | 50 µg | Daily topical drop for a maximum of 6 weeks | Safe | Effective |
Lang et al. (2006) [42] | PD | 34 (17) | GDNF | 14 µg | Daily intraputamenal continuous infusion for 6 months | Safe | Not effective |
Sorenson et al. (2008) [43] | ALS | 302 (150) | IGF-I | 0.05 mg/kg | Twice daily s/c injections for 2 years | Safe | Not effective |
Zhang et al. (2011) [50] | Macular degeneration | 36 (24) | CNTF | 5 or 10 ng daily release | Intraocular encapsulated cell implant for 12 months | Safe | Effective |
Birch et al. (2013) [47] | Retinitis pigmentosa | 266 (133) | CNTF3 CNTF4 | 5 or 20 ng daily release | Intraocular encapsulated cell implant for 12 months | Safe | Not effective |
Nakagawa et al. (2014) [51] | Sudden deafness | 118 (60) | IGF-I | 10 mg/mL | Intratympanic Gelfoam | Safe | Effective |
Rolan et al. (2015) [46] | Unilateral sciatica | 48 (36) | GDNF | 0.3, 1, 3, 10, 25, 50, 100, 200, 400, 800 μg/kg | i/v or s/c injection of a single dose | Safe | Not effective |
Characteristics | Included, n (%) |
---|---|
n, total patients in trials | 3974 |
n, patients in NF group | 2445 (61.5%) |
n, patients in placebo group | 1529 (38.5%) |
Age at treatment, in years (NF group) | |
Mean ± SD | 55.2 ± 10.4 |
Diagnosis, n, patients | |
ALS | 2090 (52.6%) |
Diabetic polyneuropathy | 1113 (28%) |
Retinitis pigmentosa | 266 (6.7%) |
Obesity | 173 (4.4%) |
Sudden deafness | 118 (3%) |
Parkinson’s disease | 84 (2.1%) |
Sciatica | 48 (1.2%) |
Macular degeneration | 36 (0.9%) |
Pressure ulcer of foot | 36 (0.9%) |
Guillain–Barre syndrome | 10 (0.2%) |
NF used, n, patients (NF group) | |
CNTF | 1219 (49.9%) |
NGF | 580 (23.7%) |
IGF-I | 510 (20.9%) |
GDNF | 91 (3.7%) |
BDNF | 45 (1.8%) |
Administration route, n, patients | |
s/c | 3385 (85.2%) |
Intraocular encapsulated implant | 302 (7.6%) |
Intratympanic gelfoam infiltrated | 118 (3%) |
ICV | 50 (1.3%) |
Topical | 36 (0.9%) |
Intraputamenal | 34 (0.9%) |
Intrathecal | 25 (0.6%) |
i/v | 24 (0.6%) |
Administration type, n, patients | |
Systemic | 3409 (85.8%) |
Local | 565 (14.2%) |
Duration of treatment | |
>6 months | 2669 (67.2%) |
1–6 months | 1082 (27.2%) |
<1 month | 105 (2.6%) |
Unknown | 118 (3%) |
Adverse Events in Patients Receiving NF, n, Events | Included, n (%) |
---|---|
n of patients receiving NF via injection | 1144 |
injection site pain or reaction | 699 (61.1%) |
n of patients receiving NF | 1836 |
Asthenia, fatigue, weakness | 436 (23.7%) |
Gastrointestinal disturbances a | 372 (20.3%) |
Cough | 193 (10.5%) |
Headache | 173 (9.4%) |
Mood changes b | 141 (7.7%) |
Dizziness, vertigo, incoordination | 135 (7.4%) |
Fever/chills/sweating | 134 (7.3%) |
Dyspnea/respiratory failure | 127 (6.9%) |
Weight loss/anorexia | 112 (6.1%) |
Sensation of warmth/shock/paresthesias | 98 (5.3%) |
Rhinitis | 69 (3.8%) |
Ophthalmological symptoms c | 68 (2.7%) |
Tinnitus | 51 (2.8%) |
Infection | 40 (2.2%) |
Pain other than injection site | 40 (2.2%) |
Dyskinesia | 34 (1.9%) |
Rash/pruritus | 32 (1.7%) |
Aural fullness | 32 (1.7%) |
Hypoglycemia | 21 (1.1%) |
Peripheral edema/joint swelling/hypertension/IOP | 20 (1.1%) |
Relatedness of adverse event to NF drug, n, study | |
n of studies reporting adverse events | 19 |
Yes | 8 (42.1%) |
No | 6 (31.6%) |
Some | 4 (21.1%) |
N/A | 1 (5.3%) |
Overall safety assessment, n, study | |
n of studies reporting on safety | 20 |
Safe | 15 (75%) |
Not safe | 2 (10%) |
Safe for lower doses | 3 (15%) |
Overall Efficacy Assessment, n, Study | n (%) |
---|---|
n of studies reporting on efficacy | 17 |
Effective | 6 (35.3%) |
Not effective | 11 (64.7%) |
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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Bezdjian, A.; Kraaijenga, V.J.C.; Ramekers, D.; Versnel, H.; Thomeer, H.G.X.M.; Klis, S.F.L.; Grolman, W. Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans. Int. J. Mol. Sci. 2016, 17, 1981. https://doi.org/10.3390/ijms17121981
Bezdjian A, Kraaijenga VJC, Ramekers D, Versnel H, Thomeer HGXM, Klis SFL, Grolman W. Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans. International Journal of Molecular Sciences. 2016; 17(12):1981. https://doi.org/10.3390/ijms17121981
Chicago/Turabian StyleBezdjian, Aren, Véronique J. C. Kraaijenga, Dyan Ramekers, Huib Versnel, Hans G. X. M. Thomeer, Sjaak F. L. Klis, and Wilko Grolman. 2016. "Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans" International Journal of Molecular Sciences 17, no. 12: 1981. https://doi.org/10.3390/ijms17121981