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Pooling Data from Similar Randomized Clinical Trials Comparing Latanoprost with Timolol; Medical Results and Statistical Aspects
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Two different principles were studied. 1st - statistical analysis techniques were used to obtain medical results from a patient population. 2nd - the patient population was used to study the statistical analysis techniques.

Medical conclusions: latanoprost and timolol treatment showed a statistically significant and clinically useful mean IOP-reduction in a typical worldwide clinical trial population. Latanoprost reduced the IOP 1.6 mm Hg more than timolol. The IOP-reduction was maintained with timolol and slightly enforced with latanoprost up to 6 months of treatment. The mean IOP-reduction was maintained during 2 years of latanoprost treatment. The overall risk of withdrawal due to insufficient IOP-reduction with latanoprost was 8%.

The statistical methodological issues are of a general and reoccurring character in trial design of the IOP-reduction: should the statistical hypothesis testing be based on the mean intraocular pressure (IOP) or the proportion of patients who reach a specific IOP level, should the estimate of the IOP or IOP-reduction be based on single eyes, mean of bilaterally eligible and identically treated eyes or the difference between an eye with active treatment and a placebo treated contralateral eye, and is mean of replicated recordings useful? Statistical methodological conclusions: the most effective response variable varies with the selected patient population. Therefore, the trial design process should include a comparison of the variability, test power and required sample size for the possible response variables in a sample of the target population. At minimum a statistical consideration should be done.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 54
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1235
Keywords [en]
Ophtalmology, mean intraocular pressure, target intraocular pressure, latanoprost, timolol, open-angle glaucoma, ocular hypertension, trial design
Keywords [sv]
Oftalmiatrik
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
URN: urn:nbn:se:uu:diva-3392ISBN: 91-554-5570-0 (print)OAI: oai:DiVA.org:uu-3392DiVA, id: diva2:162639
Public defence
2003-05-03, Grönwallsalen, Uppsala University Hospital, entrance 70, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-04-07 Created: 2003-04-07Bibliographically approved
List of papers
1. A pooled data analysis of three randomised, double-masked six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol
Open this publication in new window or tab >>A pooled data analysis of three randomised, double-masked six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol
2000 (English)In: European Journal of Ophthalmology, ISSN 1120-6721, E-ISSN 1724-6016, Vol. 10, no 2, p. 95-104Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

To compare the intraocular pressure (IOP) reduction by latanoprost and timolol, and to study factors of prognostic value for assessing this reduction.

METHODS:

We analyzed 829 patients included in three phase 111 studies comparing six months' treatment with 0.005% latanoprost once daily and 0.5% timolol twice daily in patients with open-angle glaucoma or ocular hypertension. Analysis of covariance controlled for differences in baseline IOP and sex was used to assess the IOP reduction.

RESULTS:

Latanoprost reduced diurnal IOP (average of morning, noon and afternoon assessments) by 7.7 mmHg (31%) and timolol by 6.5 mmHg (26%) after six months of treatment. Thus the diurnal IOP was reduced 1.2 mmHg (18%) more with latanoprost than with timolol (p<0.001). Latanoprost-treated patients showed a further decrease in morning IOP of 0.7 mmHg (9%, p<0.001) from the initial morning IOP reduction obtained at two weeks. No such further decrease in IOP was seen with timolol. Higher baseline diurnal IOP resulted in a larger diurnal reduction during treatment with both drugs (p<0.001). Diurnal IOP in women was reduced 0.7 mmHg (11%) less than males with both drugs (p<0.001).

CONCLUSIONS:

Latanoprost was more effective than timolol in reducing mean diurnal IOP. The effect after two weeks was maintained for timolol while with latanoprost there was a further, significant IOP reduction from two weeks to six months. Baseline IOP was the only factor of clinical importance found to be of prognostic value for assessing the IOP reduction.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90322 (URN)10887918 (PubMedID)
Available from: 2003-04-07 Created: 2003-04-07 Last updated: 2017-12-14Bibliographically approved
2. The effect of latanoprost compared with timolol in African-American, Asian, European, Mexican and US glaucoma or ocular hypertensive patients
Open this publication in new window or tab >>The effect of latanoprost compared with timolol in African-American, Asian, European, Mexican and US glaucoma or ocular hypertensive patients
2002 (English)In: Survey of ophthalmology, ISSN 0039-6257, E-ISSN 1879-3304, Vol. 47, no 4S1, p. 77-89Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

To study the intraocular pressure (IOP) reduction of latanoprost or timolol in a heterogeneous global population.

METHODS:

A total of 1,389 glaucoma or ocular hypertensive patients treated with 0.005% latanoprost once daily (n = 737) or 0.5% timolol twice daily (n = 652) from eight clinical trials were included. After 3-6 months of treatment, the IOP was analyzed with use of analysis of covariance.

RESULTS:

Latanoprost or timolol gave statistically significant mean diurnal IOP reduction in the African-American, Asian, Caucasian, and Mexican patients, latanoprost with 7.9 mm Hg and timolol with 6.4 mm Hg. The Asian and Mexican patients showed a larger difference in mean diurnal IOP reduction with use of the two drugs (range 1.8-3.1 mm Hg) than the European and U.S. patients (range 0.6-1.7 mm Hg, p = 0.030). Latanoprost produced similar mean diurnal IOP reduction in patients with and without previous glaucoma treatment other than prostaglandins.

CONCLUSION:

Latanoprost or timolol statistically significantly reduced the mean diurnal IOP in a heterogenous global population in eight clinical trials. The degree of reduction appeared to be clinically useful. The greatest difference in the mean diurnal IOP-lowering effect of latanoprost or timolol was observed in Mexican and Asian clinical trials.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90323 (URN)10.1016/S0039-6257(02)00310-7, (DOI)12204703 (PubMedID)
Available from: 2003-04-07 Created: 2003-04-07 Last updated: 2017-12-14Bibliographically approved
3. The Effect of Latanoprost on Intraocular Pressure During 2 Years of Treatment
Open this publication in new window or tab >>The Effect of Latanoprost on Intraocular Pressure During 2 Years of Treatment
2002 (English)In: Survey of ophthalmology, ISSN 0039-6257, E-ISSN 1879-3304, Vol. 47, no S1, p. 65-76Article in journal (Refereed) Published
Abstract [en]

Our objective was to study the intraocular pressure (IOP) in open-angle glaucoma or ocular hypertensive patients during long-term treatment with latanoprost. A total of 532 patients treated with 0.005% latanoprost were enrolled, including 493 and 113 patients treated for 6 and 24 months, respectively. Mean IOP was analyzed with the analysis of variance technique. The risk of treatment failure was analyzed with survival analysis technique. After 2 weeks of latanoprost treatment, the mean IOP was reduced 8.2 (32%) and 8.9 (34%) mm Hg in the subgroups of patients treated for 6 and 24 months, respectively. The change in mean IOP during 2 years of latanoprost treatment was not statistically significant (p = 0.15). Patients with primary open-angle glaucoma or ocular hypertension showed an 86% and 97% chance of receiving a sufficient IOP reduction with latanoprost (p < 0.01), repectively. The initial mean IOP reduction was maintained throughout the 2 years of treatment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90324 (URN)10.1016/S0039-6257(02)00301-6 (DOI)12204702 (PubMedID)
Available from: 2003-04-07 Created: 2003-04-07 Last updated: 2017-12-14Bibliographically approved
4. Which endpoint: mean intraocular pressure or proportion of successful patients?
Open this publication in new window or tab >>Which endpoint: mean intraocular pressure or proportion of successful patients?
2003 (English)In: Journal of glaucoma, ISSN 1057-0829, E-ISSN 1536-481X, Vol. 12, no 4, p. 321-332Article in journal (Refereed) Published
Abstract [en]

A reduction in intraocular pressure in clinical trials can be determined through the mean intraocular pressure, through the proportion of patients who have the intraocular pressure reduced to a specific target intraocular pressure, or both. Since both these possible endpoints measure the shift of 2 intraocular pressure distributions, we recommend that only one of them be tested. In general, testing the difference between mean-values is much more efficient than testing the difference between proportions. However, proportions of successful patients are valuable in showing the clinical implication of a reduction in mean intraocular pressure, particularly when evaluating a moderate pressure reduction. The effect of a small mean intraocular pressure reduction on the probability to reach the target intraocular pressure is pointed out, particularly the fact that it can be substantial even if the mean reduction is smaller than the measurement error.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90325 (URN)12897577 (PubMedID)
Available from: 2003-04-07 Created: 2003-04-07 Last updated: 2017-12-14Bibliographically approved
5. Estimating mean intraocular pressure of a group of patients; lessons learned by analyzing clinical trials of open-angle or ocular hypertensive patients
Open this publication in new window or tab >>Estimating mean intraocular pressure of a group of patients; lessons learned by analyzing clinical trials of open-angle or ocular hypertensive patients
In: Journal of GlaucomaArticle in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90326 (URN)
Available from: 2003-04-07 Created: 2003-04-07Bibliographically approved

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